Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
Up to 1 year
Other  drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitor: Atorvastatina, rosuvastatin ↑Atorvastatin ↑Rosuvastatin Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethin-dronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. * Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours.
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 4 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
Antiretroviral agents
Protease inhibitor:
  atazanavir
↓atazanavir concentration
↑ tenofovir concentration
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir concentration
↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir concentration
↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc concentration Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant concentration
↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion concentration The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole concentration
↓ hydroxy-itraconazole concentration
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole concentration Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole concentration Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin concentration
↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  rifampin
↓ efavirenz concentration If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem concentration
↓ desacetyl diltiazem concentration
↓ N-monodes-methyl diltiazem concentration
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin concentration
↓ pravastatin concentration
↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Amiodarone, verapamil, diltiazem
   Do not exceed 10 mg simvastatin daily
   Amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily,
7 days
800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Digoxin concentrations increased > 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
quinine, rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studies but reported no significant changes on digoxin exposure.
No additional actions are required.     
NA – Not available/reported


Table name:
Drugs that Affect Renal Function Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].

The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:

Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class:
Specific Drugs
Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment
a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
b See Contraindications (4), Table 3 for orally administered midazolam.
c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
didanosine buffered formulations enteric-coated (EC) capsules
↓ atazanavir
↓ didanosine
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓ atazanavir
↑ tenofovir
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine ↓ atazanavir
↑ nevirapine
Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
Protease Inhibitors: ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
Protease Inhibitors: others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
Other Agents
Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: ketoconazole, itraconazole REYATAZ/ritonavir:
↑ ketoconazole
↑ itraconazole
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Antifungals: voriconazole Effect is unknown Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ:
Treatment of gout flares:
Antimycobacterials: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir
↑ bosentan
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑ rosuvastatin
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
                        OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
    In treatment-experienced patients:
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol
↑ norgestimatec
↑ ethinyl estradiol
↑ norethindroned
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
     Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
     Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
  REYATAZ/ritonavir
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine
↑ norbuprenorphine
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
  Use of PDE5 inhibitors for erectile dysfunction:         Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
        Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
    In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of
Rilpivirine
or Concomitant Drug
Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosineThe interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily. ↔ rilpivirine
↔ didanosine
No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI
(delavirdine)
↑ rilpivirine
↔ delavirdine
It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.

Other NNRTIs
(efavirenz, etravirine, nevirapine)
↓ rilpivirine
↔ other NNRTIs
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)
darunavir/ritonavir ↑ rilpivirine
↔ boosted darunavir
Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir.
lopinavir/ritonavir ↑ rilpivirine
↔ boosted lopinavir
Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir.
other boosted PIs
(atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir)
↑ rilpivirine
↔ boosted PI
Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
unboosted PIs
(atazanavir, fosamprenavir, indinavir, nelfinavir)
↑ rilpivirine
↔ unboosted PI
Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
Other Agents
Antacids:
antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)

The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.

↓ rilpivirine
(concomitant intake)
Azole Antifungal Agents:
fluconazole
itraconazole
ketoconazole
posaconazole
voriconazole
↑ rilpivirine
↓ ketoconazole
Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.
H2-Receptor Antagonists:
cimetidine
famotidine
nizatidine
ranitidine
↔ rilpivirine
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
The combination of EDURANT and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.

↓ rilpivirine
(famotidine taken 2 hours before rilpivirine)
Macrolide or ketolide antibiotics:
clarithromycin
erythromycin
telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:
methadone
↓ R(-) methadone
↓ S(+) methadone
No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
TABLE 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT) Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0–∞
Fluvoxamine
(CYP1A2 inhibitor)
25 mg twice daily for 8 days 5 mg Single Dose +13% +29% Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine
(CYP2D6 inhibitor)
20 mg once daily for 9 days 5 mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor) 75 mg Single Dose 5 mg Single Dose +17% +10% No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor) 800 mg twice daily for 8 days 5 mg Single Dose –13% +1% No SAPHRIS dose adjustment required
Carbamazepine
(CYP3A4 inducer)
400 mg twice daily for 15 days 5 mg Single Dose –16% –16% No SAPHRIS dose adjustment required
Valproate
(UGT1A4 inhibitor)
500 mg twice daily for 9 days 5 mg Single Dose 2% –1% No SAPHRIS dose adjustment required


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor:
 Fosamprenavir
 calcium

↓ amprenavir
Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
 Atazanavir sulfate

↓ atazanavir*
Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime).
Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor:
 Indinavir

↓ indinavir*
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor:
 Lopinavir/ritonavir

↓ lopinavir*
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor:
 Ritonavir

↑ ritonavir*
↑ efavirenz*
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor:
 Saquinavir

↓ saquinavir*
Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI:
 Other NNRTIs
↑ or ↓ efavirenz
and/or NNRTI
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist:
 Maraviroc

↓ maraviroc*
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor:
 Raltegravir

↓ raltegravir*
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 Boceprevir

↓ boceprevir*
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 Telaprevir

↓ telaprevir*
↓ efavirenz*
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
 Warfarin

↑ or ↓ warfarin
Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants:
 Carbamazepine

↓ carbamazepine*
↓ efavirenz*

There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
 Phenytoin
 Phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
 Bupropion

↓ bupropion*

The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
 Sertraline ↓ sertraline* Increases in sertraline dosage should be guided by clinical response.
Antifungals:
 Voriconazole

↓ voriconazole*
↑ efavirenz*

SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .]

 Itraconazole

↓ itraconazole*
↓ hydroxyitraconazole*

Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
 Ketoconazole ↓ ketoconazole Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
 Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
 Clarithromycin

↓ clarithromycin*
↑ 14-OH metabolite*
Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials:
 Rifabutin

↓ rifabutin*
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
 Rifampin ↓ efavirenz* If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers:
 Diltiazem

↓ diltiazem*
↓ desacetyl diltiazem*
↓ N-monodesmethyl diltiazem*
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)
↓ calcium channel blocker
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  Atorvastatin
  Pravastatin
  Simvastatin


  ↓ atorvastatin*
↓ pravastatin*
↓ simvastatin*
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral
 Ethinyl estradiol/
 Norgestimate

↓ active metabolites
of norgestimate*

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant
 Etonogestrel

↓ etonogestrel

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A

↓ immunosuppressant
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic:
 Methadone

↓ methadone*
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
blood dyscrasias —    diarrhea      hyperthyroidism
   see  CONTRAINDICATIONS elevated temperature   poor nutritional state    
cancer  hepatic disorders   steatorrhea
collagen vascular disease     infectious hepatitis   vitamin K deficiency
congestive heart failure     jaundice


Table name:
Classes of Drug
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
   5-lipoxygenase Inhibitor    Antiplatelet Drugs/Effects    Leukotriene Receptor Antagonist
   Adrenergic Stimulants, Central    Antithyroid Drugs    Monoamine Oxidase Inhibitors
   Alcohol Abuse Reduction    Beta-Adrenergic Blockers    Narcotics, prolonged
       Preparations    Cholelitholytic Agents    Nonsteroidal Anti-
   Analgesics    Diabetes Agents, Oral          Inflammatory Agents
   Anesthetics, Inhalation    Diuretics    Proton Pump Inhibitors
   Antiandrogen    Fungal Medications,     Psychostimulants
   Antiarrhythmics        Intravaginal, Systemic    Pyrazolones
   Antibiotics    Gastric Acidity and Peptic    Salicylates
      Aminoglycosides (oral)        Ulcer Agents    Selective Serotonin
      Cephalosporins, parenteral    Gastrointestinal          Reuptake Inhibitors
      Macrolides        Prokinetic Agents    Steroids, Adrenocortical
      Miscellaneous        Ulcerative Colitis Agents    Steroids, Anabolic (17-Alkyl
      Penicillins, intravenous,    Gout Treatment Agents           Testosterone Derivatives)
         high dose    Hemorrheologic Agents    Thrombolytics
      Quinolones (fluoroquinolones)    Hepatotoxic Drugs    Thyroid Drugs
      Sulfonamides, long acting    Hyperglycemic Agents    Tuberculosis Agents
      Tetracyclines    Hypertensive Emergency  Agents              Uricosuric Agents
   Anticoagulants    Hypnotics    Vaccines
   Anticonvulsants    Hypolipidemics    Vitamins
   Antidepressants       Bile Acid-Binding Resins
   Antimalarial Agents       Fibric Acid Derivatives
   Antineoplastics       HMG-CoA Reductase   Inhibitors
   Antiparasitic/Antimicrobials
Specific Drugs Reported
   acetaminophen    fenoprofen    paroxetine
   alcoholIncreased and decreased PT/INR responses have been reported.    fluconazole    penicillin G, intravenous
   allopurinol    fluorouracil    pentoxifylline
   aminosalicylic acid    fluoxetine    phenylbutazone
   amiodarone HCl    flutamide    phenytoin
   argatroban    fluvastatin    piperacillin
   aspirin    fluvoxamine    piroxicam
   atenolol    gefitinib    pravastatin
   atorvastatin    gemfibrozil    prednisone
   azithromycin    glucagon    propafenone
   bivalirudin    halothane    propoxyphene
   capecitabine    heparin    propranolol
   cefamandole    ibuprofen    propylthiouracil
   cefazolin    ifosfamide    quinidine
   cefoperazone    indomethacin    quinine
   cefotetan    influenza virus vaccine    rabeprazole
   cefoxitin    itraconazole    ranitidine
   ceftriaxone    ketoprofen    rofecoxib
   celecoxib    ketorolac    sertraline
   cerivastatin    lansoprazole    simvastatin
   chenodiol    lepirudin    stanozolol
   chloramphenicol    levamisole    streptokinase
   chloral hydrate    levofloxacin    sulfamethizole
   chlorpropamide    levothyroxine    sulfamethoxazole
   cholestyramine    liothyronine    sulfinpyrazone
   cimetidine    lovastatin    sulfisoxazole
   ciprofloxacin    mefenamic acid    sulindac
   cisapride    methimazole    tamoxifen
   clarithromycin    methyldopa    tetracycline
   clofibrate    methylphenidate    thyroid
   warfarin sodium overdose    methylsalicylate ointment (topical)    ticarcillin
   cyclophosphamide    metronidazole    ticlopidine
   danazol    miconazole     tissue plasminogen
   dextran    (intravaginal, oral, systemic)    activator (t-PA)
   dextrothyroxine    moricizine hydrochloride    tolbutamide
   diazoxide    nalidixic acid    tramadol
   diclofenac    naproxen    trimethoprim/sulfamethoxazole
   dicumarol    neomycin    urokinase
   diflunisal    norfloxacin    valdecoxib
   disulfiram    ofloxacin    valproate
   doxycycline    olsalazine    vitamin E
   erythromycin    omeprazole    zafirlukast
   esomeprazole    oxandrolone    zileuton
   ethacrynic acid    oxaprozin
   ezetimibe    oxymetholone
   fenofibrate    pantoprazole


Table name:
edema hypothyroidism 
hereditary coumarin resistance nephrotic syndrome
hyperlipemia


Table name:
Classes of Drugs
also: diet high in vitamin K unreliable PT/INR determinations
   Adrenal Cortical Steroid Inhibitors     Antipsychotic Medications    Hypolipidemics
   Antacids    Antithyroid Drugs    Bile Acid-Binding Resins
   Antianxiety Agents
   Antiarrhythmics
   Barbiturates
   Diuretics
   HMG-CoA Reductase Inhibitors
   Anticonvulsants    Enteral Nutritional Supplements     Immunosuppressives
   Antidepressants    Fungal Medications, Systemic    Oral Contraceptives,
   Antihistamines    Gastric Acidity and Peptic  Ulcer Agents    Estrogen Containing
   Antineoplastics    Hypnotics    Selective Estrogen Receptor Modulators
   Steroids, Adrenocortical
   Tuberculosis Agents
   Vitamins
Specific Drugs Reported:
   alcoholIncreased and decreased PT/INR responses have been reported.    warfarin sodium underdosage    phenytoin
   aminoglutethimide    cyclophosphamide    pravastatin
   amobarbital    dicloxacillin    prednisone
   atorvastatin    ethchlorvynol    primidone
   azathioprine    glutethimide    propylthiouracil
   butabarbital    griseofulvin    raloxifene
   butalbital    haloperidol    ranitidine
   carbamazepine    meprobamate    rifampin
   chloral hydrate    6-mercaptopurine    secobarbital
   chlordiazepoxide    methimazole    spironolactone
   chlorthalidone    moricizine hydrochloride    sucralfate
   cholestyramine    nafcillin    trazodone
   clozapine    paraldehyde    vitamin C (high dose)
   corticotropin    pentobarbital    vitamin K
   cortisone    phenobarbital


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
  dietary digestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
Antiretroviral agents
Protease inhibitor:
  atazanavir
↓atazanavir concentration
↑ tenofovir concentration
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
 
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir concentration
↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir concentration
↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI:
  didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant concentration
↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:
  sertraline
↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole concentration
↓ hydroxy-itraconazole concentration
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole concentration Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective:
  clarithromycin
↓ clarithromycin concentration
↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  rifampin
↓ efavirenz
concentration
Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers:
  diltiazem
↓ diltiazem concentration
↓ desacetyl diltiazem concentration
↓ N-monodes-methyl diltiazem concentration
Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin concentration
↓ pravastatin concentration
↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  Ethinyl
  estradiol/Norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  Etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 4 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class:
Drug name
Effect on Concentration of Tipranavir or Concomitant Drug Clinical Comment
↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict

HIV-1 Antiviral Agents
Fusion Inhibitors:
 
 
Enfuvirtide ↑ Tipranavir At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Nucleoside Reverse Transcriptase Inhibitors:
 
 
Abacavir ↓ Abacavir AUC by approximately 40% Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
 
Didanosine (EC) ↓ Didanosine Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours.
 
Zidovudine ↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease Inhibitors (co-administered with 200 mg of ritonavir):
 
 
Fosamprenavir
Lopinavir
Saquinavir
↓ Amprenavir
↓ Lopinavir
↓ Saquinavir
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.

Protease Inhibitors (co-administered with 100 mg of ritonavir):
 
 
Atazanavir ↓ Atazanavir
↑ Tipranavir
 
Virus Integrase Strand Transfer Inhibitors:
 
   
Raltegravir ↓ Raltegravir APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended.

Agents for Opportunistic Infections
 
Antifungals:
 
 
Fluconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.
 
Itraconazole
Ketoconazole
↑ Itraconazole (not studied)
↑ Ketoconazole (not studied)
Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended.
 
Voriconazole ↕ Voriconazole (not studied) Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
Antimycobacterials:
 
 
Clarithromycin ↑ Tipranavir, ↑ Clarithromycin,
↓ 14-hydroxy-clarithromycin metabolite
No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.
 
  For patients with renal impairment the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%.
 
Rifabutin Tipranavir not changed, ↑ Rifabutin
↑ Desacetyl-rifabutin
Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
 
Other Agents Commonly Used
 
Anticonvulsants:
 
Carbamazepine
Phenobarbital
Phenytoin
↓ Tipranavir Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.
 
Valproic Acid ↓ Valproic Acid Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly.
Antidepressants:

Trazodone


↑ Trazodone


Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
 
Desipramine Combination with APTIVUS/ritonavir not studied
↑ Desipramine
Dosage reduction and concentration monitoring of desipramine is recommended.
 
Selective Serotonin-Reuptake Inhibitors: Combination with APTIVUS/ritonavir not studied Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine
Paroxetine
Sertraline
↑ Fluoxetine
↑ Paroxetine
↑ Sertraline
 
Anti-gout

Colchicine


↑ Colchicine
Patients with renal or hepatic impairment should not be given colchicine with APTIVUS/ritonavir.

Treatment of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir : If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Benzodiazepines:
 
 
Parenterally administered midazolam ↑ Midazolam Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [ see Contraindications (4) ]. If APTIVUS is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone ↔ Buprenorphine
↓ Tipranavir
APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir Cmin was decreased approximately 40% with this combination. Dose adjustments cannot be recommended.
Calcium Channel Blockers:

Diltiazem
Felodipine
Nicardipine
Nisoldipine
Verapamil
Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp.

↕ Diltiazem
↑ Felodipine (CYP3A substrate but not P-gp substrate)
↕ Nicardipine
↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate)
↕ Verapamil
Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists   Co-administration of bosentan in patients on APTIVUS/ritonavir:

Bosentan

↑ Bosentan

In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of APTIVUS/ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir.

After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
 
 
Atorvastatin
Rosuvastatin
↑ Atorvastatin
↓ Hydroxy-atorvastatin metabolites
↑ Rosuvastatin
Avoid co-administration with atorvastatin.
Hypoglycemics:
 
 
  Combination with APTIVUS/ritonavir not studied Careful glucose monitoring is warranted.
 
Glimepiride
Glipizide
Glyburide
Pioglitazone
↔ Glimepiride (CYP 2C9)
↔ Glipizide (CYP 2C9)
↔ Glyburide (CYP 2C9)
↕ Pioglitazone (CYP 2C8 and CYP 3A4)
 
Repaglinide ↕ Repaglinide (CYP 2C8 and CYP 3A4)  
Tolbutamide ↔ Tolbutamide (CYP 2C9)

The effect of TPV/ritonavir on CYP 2C8 substrate is not known.
 
Immunosuppressants:
 
 
  Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.
Cyclosporine
Sirolimus
Tacrolimus
↕ Cyclosporine
↕ Sirolimus
↕ Tacrolimus
 
Inhaled beta agonist:

Salmeterol


↑ Salmeterol
Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/Nasal Steroids:
 
 
Fluticasone ↑ Fluticasone Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic Analgesics:
 
 
Meperidine Combinations with APTIVUS/ritonavir not studied
↓ Meperidine, ↑ Normeperidine
Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
 
Methadone ↓ Methadone
↓ S-Methadone, ↓ R-Methadone
Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.
 
Oral Contraceptives/Estrogens:
 
 
Ethinyl estradiol ↓ Ethinyl estradiol concentrations by 50% Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash.
Proton Pump Inhibitors:
 
 
Omeprazole ↓ Omeprazole, ↔ Tipranavir Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.
PDE-5 Inhibitors:  
  Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction).
 
Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Sildenafil ↑ Sildenafil (not studied) Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):

Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4.2)].

The following dose adjustments are recommended for use of tadalafil (Adcirca) with APTIVUS/ritonavir:
Tadalafil ↑ Tadalafil with first dose APTIVUS/ritonavir
↔ Tadalafil at APTIVUS/ritonavir steady-state
Co-administration of tadalafil (Adcirca) in patients on APTIVUS/ritonavir:

In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Vardenafil ↑ Vardenafil (not studied) Co-administration of APTIVUS/ritonavir in patients on tadalafil (Adcirca):

Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE-5 inhibitors for erectile dysfunction:

Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Warfarin ↔ S-Warfarin Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy.


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
     
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
     
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
     
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events
and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By NIZORAL® This list is not all-inclusive.
Systemic exposure to these drugs is increased significantly by the addition of ketoconazole:
Concomitant use with ketoconazole is contraindicated.
Alprazolam, midazolam, triazolam HMG-CoA reductase inhibitors
(lovastatin, simvastatin)
Cisapride Nisoldipine
Dofetilide Pimozide
Eplerenone Quinidine
Ergot alkaloids (ergotamine, dihydroergotamine)
Systemic exposure to these drugs is increased by ketoconazole:
Careful monitoring, with possible adjustment in dosage, is recommended.
Alfentanil, fentanyl, sulfentanil Indinavir, saquinavir
Amlodipine, felodipine, nicardipine, nifedipine Methylprednisolone
Bosentan Rifabutin
Buspirone Sildenafil
Busulfan Sirolimus (co-administration not recommended)
Carbamazepine Tacrolimus
Cilostazol Telithromycin
Cyclosporine Tolterodine
Digoxin Trimetrexate
Docetaxel, paclitaxel Verapamil
Oral anti-coagulants Vinca alkaloids (vincristine, - vinblastine, vinorelbine)


Table name:
Table 2. Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of NIZORAL®
Systemic exposure to ketoconazole is reduced significantly by these drugs:
Concomitant use with ketoconazole is not recommended.
* This list is not all-inclusive.
Carbamazepine Phenytoin
Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate) Rifampin, rifabutin, isoniazid
Nevirapine
Systemic exposure to ketoconazole is increased significantly by this drug:
Dose reduction of ketoconazole should be considered
Ritonavir


Table name:

albuterol, systemic and inhaled

mebendazole

amoxicillin

medroxyprogesterone

ampicillin, with or without

methylprednisolone

sulbactam

metronidazole

atenolol

metoprolol

azithromycin

nadolol

caffeine, dietary ingestion

nifedipine

cefaclor

nizatidine

co-trimoxazole (trimethoprim and

sulfamethoxazole)

norfloxacin

ofloxacin

diltiazem

omeprazole

dirithromycin

prednisone, prednisolone

enflurane

ranitidine

famotidine

rifabutin

felodipine

roxithromycin

finasteride

Sorbitol (purgative doses do not inhibit

hydrocortisone

theophylline absorption)

isoflurane

sucralfate

isoniazid

terbutaline, systemic

isradipine

terfenadine

influenza vaccine

tetracycline

ketoconazole

tocainide

lomefloxacin

 


Table name:
Table 3: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Valuesa
Drug Didanosine Dosage n AUC of Didanosine (90% CI) Cmax of Didanosine (90% CI)
tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 26 ↑ 48%
(31, 67%)
↑ 48%
(25, 76%)
tenofovir,b  300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 25 ↑ 60%
(44, 79%)
↑ 64%
(41, 89%)
tenofovir,b  300 mg once daily with a light mealc 200 mg single dose with tenofovir and a light meal 250 mg single dose with tenogovir and a light meal 325 mg single dose with tenofovir and a light meal 33 33 33 ↑ 16%
(6, 27%)d
↔(-13, 5%)e    ↑ 13% (3, 24%)
↓ 12%
(-25, 3%)d
↓ 20%
(-32, -7%)e
↓ 11%
(-24, 4%)e
↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60kg with creatinine clearance ≥60
mL/min.
b tenofovir disporoxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with didanosine delayed-release capsules 250 mg administered alone under
fasting coniditions.
e Compared with didanosine delayed-release capsules 400 mg administered alone under
fasting conditions.


Table name:
Table 4: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Valuesa
↔ Indicates no change, or mean increase or decrease of less than 10%.
* The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. All studies conducted in healthy volunteers ≥ 60 kg with creatinine clearance ≥ 60 mL/min. Tenofovir disoproxil fumarate. § 373 kcalories, 8.2 grams fat.
    Drug Didanosine Dosage n AUC of Coadministered Drug Cmax of Coadministered Drug
ciprofloxacin,
750 mg single dose
indinavir,
800 mg single dose
ketoconazole,
200 mg single dose
tenofovir,
300 mg once daily
with a light meal§
tenofovir,
300 mg once daily
with a light meal§
400 mg single dose 400 mg single dose 400 mg single dose 400 mg single dose fasting 2h before tenofovir 400 mg single dose with tenofovir anda light meal 16 23 21 25 25


Table name:
Table 5: Results of Drug Interaction Studies with Buggered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine plasma AUC and Cmax Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS, Drug Interactions )
Drug Didanosine Dosage n AUC Didanosine (95% CI) Cmax of Didanosine (95% CI)
allopurinol, Renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232%
healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69%
ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA
methadone, chronic maintenance dose 200 mg single dose 16, 10a ↓57% ↓66%
tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↑44% (31, 59%)d ↔28% (11, 48%)d
No Clinically Significant Interactions Observed
ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8e ↓16% ↓28%
ininavir, 800 mg single dose simultaneous 200 mg single dose 16
1 h before didanosine 200 mg single dose 16 ↓17% (-27, -7%)d ↓13% (-28, 5%)d
ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12e ↓12%
loperamide, 4 mg q6h for 1 day 300 mg single dose 12e ↓23%
metoclopramide, 10 mg single dose 300 mg single dose 12e ↑13%
ranitidine, 150 mg 2 h before didansine 375 mg single dose 12e ↑14% ↑13%
rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8e
trimethoprim, 200 mg single dose 200 mg single dose 8e ↑17% (-23, 77%)
zidovudine, 200 mg q7h for 3 days 200 mg q12h for 3 days 8e
↑ indicates increase
↓ indicates decrease
↔ indicates no change, or mean increase or decrease of <10%.
a Parellel-group design; entries are subjects receiving combination and control regimens, respectively.
b tenogovir disoproxil fumarate
c patients <60 kg with creatinine clearance >60 mL/min.
d 90% CI
e HIV-infected patients
N/A Not available


Table name:
Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
No Clinically Significant Interaction Observed
Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose 200 mg q12h for 14 days 6a
delaviridine, 400 mg single dose simultaneous 125 or 200 mg q12h 12a ↓32%b ↓53%b
1 hr before didanosine 125 or 200 mg q12h 12a ↑20% ↑18%
ganciclovir, 1000 mg q8h, 2h after didanosine 200 mg q12h 12a ↓21% NA
nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12%
ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16%
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↑17%
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%)
tenofovir,C 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days 14
trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%)
↑ indicates increase. ↓indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%.
aHIV-infected patients.
bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules.
ctenofovir disoproxil fumarate.
dpatients <60 kg with creatinine clearance >60 mL/min.
NA Not available


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓Amprenavir

↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir

↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz












The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Delavirdine
Etravirine
Rilpivirine



Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.










Other Agents
Analgesics:
Methadone*



↓ Methadone





Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.



Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*



↓ Clarithromycin

↑ 14-OH clarithromycin



Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.



Rifabutin*



↑Rifabutin



Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.



Rifampin*



↓ Nevirapine



Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.



Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide

Plasma concentrations of nevirapine and the anticonvulsant may be decreased.

Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:
Fluconazole*



↑Nevirapine



Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.



Ketoconazole*



↓ Ketoconazole



Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Itraconazole



↓ Itraconazole



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.



Antithrombotics:
Warfarin
Plasma concentrations may be decreased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be increased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
Delavirdine*
↑ Saquinavir

Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor:
Efavirenz,
nevirapine
↓ Saquinavir
↔ Efavirenz


Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor:
Atazanavir
INVIRASE/ritonavir
↑ Saquinavir
↑ Ritonavir
↔ Atazanavir
Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir [see Warnings and Precautions (5.2)].
HIV-1 protease inhibitor:
Indinavir
↑ Saquinavir

Effect on indinavir is not well established
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor:
Lopinavir/ritonavir (coformulated tablet)
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.

Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor:
Tipranavir/ritonavir
↓ Saquinavir
Combining saquinavir with tipranavir/ritonavir is not recommended.

HIV-1 fusion inhibitor:
Enfuvirtide
Saquinavir soft gel capsules/ritonavir
↔ enfuvirtide
No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
HIV-1 CCR5 antagonist:
Maraviroc
↑ Maraviroc Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Ibutilide
Sotalol
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Anticoagulant:
Warfarin
↑ Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin
↓ Saquinavir

Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-gout:
Colchicine
↑ Colchicine Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Anti-infective:
Clarithromycin
↑ Saquinavir
↑ Clarithromycin
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Erythromycin
Halofantrine
Pentamidine
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Antifungal:
Ketoconazole,
itraconazole
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial:
Rifabutin
↔ Saquinavir
↑ Rifabutin
↔ Ritonavir

No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin.

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination.

Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepines :
Alprazolam, clorazepate, diazepam, flurazepam
↑ Benzodiazepines Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine :
Intravenously administered Midazolam
↑ Midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers :
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
↑ Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ Saquinavir
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.
Digitalis Glycosides: Digoxin ↑ Digoxin

Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists:
Bosentan
↑ Bosentan Coadministration of bosentan in patients on INVIRASE/ritonavir:

In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir.

After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist:
Salmeterol
↑ Salmeterol Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid:
Fluticasone
INVIRASE/ritonavir
↑ Fluticasone
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
HMG-CoA reductase inhibitors :
Atorvastatin
↑ Atorvastatin
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.
Immunosuppressants :
Cyclosporine, tacrolimus, rapamycin
↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadone
↓ Methadone Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.

Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Neuroleptics:
Clozapine
Haloperidol
Mesoridazine
Phenothiazines
Thioridazine
Ziprasidone
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives:
Ethinyl estradiol
↓ Ethinyl estradiol Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors):
Sildenafil, vardenafil, tadalafil
↑ Sildenafil
↔ Saquinavir

↑ Vardenafil
↑ Tadalafil

Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca®) with INVIRASE/ritonavir:

Coadministration of Adcirca in patients on INVIRASE/ritonavir:

In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on Adcirca:

Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, imipramine
↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole ↑ Saquinavir When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products:
St. John's wort (hypericum perforatum)
↓ Saquinavir Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Garlic Capsules ↓ Saquinavir Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors
(e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone),gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
  Concomitant Drug   Effect on Concentration of Lamotrigine or Concomitant Drug   Clinical Comment
  Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓ lamotrigine   Decreased lamotrigine levels approximately 50%.
     ↓ levonorgestrel   Decrease in levonorgestrel component by 19%.
  Carbamazepine (CBZ) and CBZ epoxide   ↓ lamotrigine   Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
     ? CBZ epoxide   May increase CBZ epoxide levels
  Phenobarbital/Primidone   ↓ lamotrigine   Decreased lamotrigine concentration approximately 40%.
  Phenytoin (PHT)   ↓ lamotrigine   Decreased lamotrigine concentration approximately 40%.
  Rifampin   ↓ lamotrigine   Decreased lamotrigine AUC approximately 40%.
  Valproate   ↑ lamotrigine   Increased lamotrigine concentrations slightly more than 2-fold.
     ? valproate   Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs
a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL.
b) Maximum changes predicted to be in children and in patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent.
c) Larger effects in children at high doses/concentrations of AEDs.
d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance.
e) All compounds of the benzodiazepine class were pooled to examine for 'class effect' on BANZEL clearance.
AED Co-administered Influence of Rufinamide on AED concentrationa) Influence of AED on Rufinamide concentration
Carbamazepine Decrease by 7 to 13%b) Decrease by 19 to 26%
Dependent on dose of carbamazepine
Lamotrigine Decrease by 7 to 13%b) No Effect
Phenobarbital Increase by 8 to 13%b) Decrease by 25 to 46% c), d)
Independent of dose or concentration of Phenobarbital
Phenytoin Increase by 7 to 21%b) Decrease by 25 to 46% c), d)
Independent of dose or concentration of phenytoin
Topiramate No Effect No Effect
Valproate No Effect Increase by <16 to 70% c)
Dependent on concentration of valproate
Primidone Not Investigated Decrease by 25 to 46% c), d)
Independent of dose or concentration of primidone
Benzodiazepinese) Not Investigated No Effect


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 5. Significant Interactions Between POTIGA and Concomitant Antiepileptic Drugs
AED Dose of AED (mg/day) Dose of POTIGA (mg/day) Influence of POTIGA on AED Influence of AED on POTIGA Dosage Adjustment
Carbamazepinea,b 600-2,400 300-1,200 None 31% decrease in AUC, 23% decrease in Cmax consider an increase in dosage of POTIGA when adding carbamazepinec
Phenytoina,b 120-600 300-1,200 None 34% decrease in AUC, 18% decrease in Cmax consider an increase in dosage of POTIGA when adding phenytoinc


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed
* Change relative to reference


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration
of Lamotrigine or
Concomitant Drug
Clinical Comment 
Estrogen-containing oral 
contraceptive preparations
containing 30 mcg 
ethinylestradiol and 150 mcg
levonorgestrel 
↓ lamotrigine 


↓ levonorgestrel 
Decreased lamotrigine levels 
approximately 50%. 

Decrease in levonorgestrel 
component by 19%. 
Carbamazepine and
carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine
  epoxide 
Addition of carbamazepine 
decreases lamotrigine 
concentration approximately 40%. 
May increase carbamazepine
epoxide levels. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Rifampin 
↓ lamotrigine
Decreased lamotrigine 
AUC approximately 40%. 
Valproate 
↑ lamotrigine 


? valproate 
Increased lamotrigine 
concentrations slightly more than 
2-fold. 
Decreased valproate concentrations 
an average of 25% over a 3-week 
period then stabilized in healthy 
volunteers; no change in controlled 
clinical trials in epilepsy patients. 


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%

↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%

? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold

? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0–24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids Cross-tolerance and mutual potentiation
Naltrexone Oral THC effects were enhanced by opioid receptor blockade.
Alcohol Increase in the positive subjective mood effects of smoked marijuana


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
 Erythromycin
(500 mg every 8 hrs)
 +82%  +109%
 Ketoconazole
(400 mg once daily)
 +135%  +164%


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 9: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 12 and 13]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents:
NS3-4A protease inhibitors:

boceprevir
telaprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comments
    HIV-Antiviral Agents
HIV-1 Protease Inhibitor:
atazanavir
When co-administered with reduced doses of atazanavir and ritonavir
↑ atazanavir (↑ AUC, ↑ Cmax, ↑ Cmin)
Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor:
darunavir
When co-administered with reduced doses of ritonavir
↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor:
fosamprenavir
When co-administered with reduced doses of ritonavir
↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Lexiva® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor:
indinavir
When co-administered with reduced doses of indinavir and ritonavir
↑ indinavir (↔ AUC, ↓ Cmax, ↑ Cmin)
Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR.
Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor:
saquinavir
When co-administered with reduced doses of ritonavir
↑ saquinavir
(↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Invirase® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.
Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor:
tipranavir
When co-administered with reduced doses of ritonavir
↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ ritonavir (↑AUC, ↑Cmax, ↑ Cmin) Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).
Integrase Inhibitor:
Raltegravir
↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic:
tramadol, propoxyphene
  A dose decrease may be needed for these drugs when co-administered with ritonavir.
Anesthetic:
meperidine
↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics:
disulfiram/metronidazole
  Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics:
disopyramide, lidocaine, mexiletine
↑antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents:
dasatinib, nilotinib,
vincristine, vinblastine
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
↓ R-warfarin
↓↑ S-warfarin
Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated.
Anticoagulant:
rivaroxaban
↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine, clonazepam, ethosuximide
↑anticonvulsants Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants:
divalproex, lamotrigine, phenytoin
↓anticonvulsants Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants:
nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline
↑antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite, hydroxybupropion
Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
desipramine
↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetic:
dronabinol
↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal:
ketoconazole
itraconazole
voriconazole
↑ ketoconazole
↑ itraconazole

↓ voriconazole
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with ritonavir.

Treatment of gout flares-co-administration of colchicine in patients on ritonavir:

0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment the following dosage adjustments should be considered:
 • For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.
 • For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
rifabutin
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial:
rifampin
↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic:
quinine
↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.
β-Blockers:
metoprolol, timolol
↑ Beta-Blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator:
theophylline
↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil
↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants:
cyclosporine, tacrolimus, sirolimus (rapamycin)
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Inhaled or Intranasal
Steroid: e.g.
fluticasone
budesonide
↑ glucocorticoids Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone
fentanyl
↓ methadone
↑ fentanyl
Dosage increase of methadone may be considered.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Neuroleptics:
perphenazine, risperidone, thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol
↓ ethinyl estradiol Alternate methods of contraception should be considered.
PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see Contraindications (4) ].

The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir:

Co-administration of ADCIRCA in patients on ritonavir:

In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:

 • Sildenafil: 25 mg every 48 hours
 • Tadalafil: 10 mg every 72 hours
 • Vardenafil: 2.5 mg every 72 hours.
Use with increased monitoring for adverse events.
Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem
↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics:
Parenteral midazolam
↑ midazolam Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids (systemic): e.g.
budesonide
dexamethasone, prednisone
 ↑ glucocorticoids Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Stimulant:
methamphetamine
↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug
Dosing Schedule
Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)
Risperidone Dose Recommendation
 
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. Do not exceed 8 mg/day
 
20 mg/day
4 mg/day
1.6
-
 
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan:
Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].


The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:


Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.


Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class:
Specific Drugs
Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment
a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
b See Contraindications (4), Table 3 for orally administered midazolam.
c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
didanosine buffered formulations enteric-coated (EC) capsules
↓ atazanavir
↓ didanosine
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓ atazanavir
↑ tenofovir
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
nevirapine ↓ atazanavir
↑ nevirapine
Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors:
saquinavir (soft gelatin capsules)
↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors:
boceprevir
↓ atazanavir
↓ ritonavir
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended.
telaprevir ↓ telaprevir
↑ atazanavir
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
Other Agents
Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics:
carbamazepine
↓ atazanavir
↑ carbamazepine
Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital ↓ atazanavir
↓ phenytoin
↓ phenobarbital
Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals:
ketoconazole, itraconazole
REYATAZ/ritonavir:
↑ ketoconazole
↑ itraconazole
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
voriconazole REYATAZ/ritonavir in subjects with a functional CYP2C19 allele:
↓ voriconazole
↓ atazanavir
REYATAZ/ritonavir in subjects without a functional CYP2C19 allele:
↑ voriconazole
↓ atazanavir
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ:
Treatment of gout flares:
Antimycobacterials: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir
↑ bosentan
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
                        OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
    In treatment-experienced patients:
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol
↑ norgestimatec
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
↑ ethinyl estradiol
↑ norethindroned
Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
     Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
  REYATAZ/ritonavir
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine
↑ norbuprenorphine
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
  Use of PDE5 inhibitors for erectile dysfunction:         Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
        Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
    In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug
(Postulated effect on CYP450/UGT)
Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0-∞
Fluvoxamine
(CYP1A2 inhibitor)
25 mg twice daily for 8 days 5-mg Single Dose +13% +29% Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine
(CYP2D6 inhibitor)
20 mg once daily for 9 days 5-mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine
(CYP1A2/2C19/3A4 inhibitor)
75-mg Single Dose 5-mg Single Dose +17% +10% No SAPHRIS dose adjustment required
Cimetidine
(CYP3A4/2D6/1A2 inhibitor)
800 mg twice daily for 8 days 5-mg Single Dose –13% +1% No SAPHRIS dose adjustment required
Carbamazepine
(CYP3A4 inducer)
400 mg twice daily for 15 days
5-mg Single Dose –16% –16% No SAPHRIS dose adjustment required
Valproate
(UGT1A4 inhibitor)
500 mg twice daily for 9 days 5-mg Single Dose 2% –1% No SAPHRIS dose adjustment required


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
  dietary digestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓lamotrigine Decreased lamotrigine levels approximately 50%.
↓levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine   Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting  Drug
Interaction

Multivalent cation-containing products including antacids, metal cation or didanosine


Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 




Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

Antidiabetic agent

Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg b.i.d. should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
HMG-CoA
Reductase Inhibitors:
atorvastatin




fluvastatin,
lovastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin




↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.


No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics:
methadone
↔ etravirine
↔ methadone
INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
vardenafil,
tadalafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Digoxin concentrations increased > 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril 58% 39%
Nitrendipine 57% 15%
Propafenone 35-85% NA
Quinidine 100% NA
Ranolazine 87% 88%
Ritonavir NA 86%
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem 20% NA
Nifedipine 45% NA
Rabeprazole 29% 19%
Telmisartan 20% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclopramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in complete heart block.


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*) Risperidone DoseRecommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6)Inhibitors        
Fluoxetine 20 mg/day 2 or 3 mg twicedaily 1.4 1.5 Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Donot exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four timesdaily 1 mg single dose 1.1 0.94 Dose adjustment not needed
           
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD
 
Concentration

(Mean Change,
90% Confidence Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Reevaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day - 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 5 Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration with Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs) +82% +109%
Ketoconazole(400 mg once daily) +135% +164%


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
AED Co-administered AED Concentration TOPAMAX Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.4, 4, 5.2, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with JUVISYNC
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 telaprevir
↓ telaprevir
↓ efavirenz
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%
↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold
? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].
The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase.
↓ Indicates decrease.
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate ↑didanosine concentration A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs ↑risk of neuropathy Use with caution.[See Warnings and Precautions (5.6)].


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓    Lamotrigine     ↓    levonorgestrel   Decreased lamotrigine levels approximately 50%.   Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓    Lamotrigine       ?    CBZ epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%.   May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓    Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓    Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓    Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑    Lamotrigine        ?   valproate   Increased Lamotrigine concentrations slightly more than 2-fold.   Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevira LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroca LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole,
posaconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc1,2
up to 40% increase3
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
   ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
   ? CBZ epoxide  May increase CBZ epoxide levels
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2-fold.
   ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,  systemic and inhaled felodipinefinasteride nizatidinenorfloxacin
amoxicillin hydrocortisone ofloxacin
ampicillin,   with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone
atenolol isradipine ranitidine
azithromycin influenza vaccine rifabutin
caffeine,   dietary ingestion ketoconazo lelomefloxacin roxithromycin sorbitol
cefaclor mebendazole         (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone    inhibit theophylline   absorption)
diltiazem metronidazole sucralfate
dirithromycin metoprolol terbutaline, systemic
enflurane nadolol terfenadine
famotidine nifedipine tetracycline
tocainide


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comment
    HIV-Antiviral Agents
HIV Protease Inhibitor:
atazanavir
When co-administered with reduced doses of atazanavir and ritonavir
↑ atazanavir (↑ AUC, ↑ Cmax, ↑ Cmin)
Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor:
darunavir
When co-administered with reduced doses of ritonavir
↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor:
fosamprenavir
When co-administered with reduced doses of ritonavir
↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Lexiva® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor:
indinavir
When co-administered with reduced doses of indinavir and ritonavir
↑ indinavir (↔ AUC, ↓ Cmax, ↑ Cmin)
Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR.
Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV Protease Inhibitor:
saquinavir
When co-administered with reduced doses of ritonavir
↑ saquinavir
(↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Invirase® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.
Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV Protease Inhibitor:
tipranavir
When co-administered with reduced doses of ritonavir
↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin)
See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ ritonavir (↑AUC, ↑Cmax, ↑ Cmin) Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).
Integrase Inhibitor: Raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic:
tramadol, propoxyphene
  A dose decrease may be needed for these drugs when co-administered with ritonavir.
Anesthetic:
meperidine
↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics:
disulfiram/ metronidazole
  Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics:
disopyramide, lidocaine, mexiletine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents:
dasatinib, nilotinib,
vincristine, vinblastine
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
↓ R-warfarin
↓↑ S-warfarin
Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated.
Anticoagulant:
rivaroxaban
↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine, clonazepam, ethosuximide
↑ anticonvulsants Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants:
divalproex, lamotrigine, phenytoin
↓ anticonvulsants Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants:
nefazodone,
selective serotonin
reuptake inhibitors
(SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline
↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite, hydroxybupropion
Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
desipramine
↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant: trazodone ↑ trazodone Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetic:
dronabinol
↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal:
ketoconazole
itraconazole
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with ritonavir.

Treatment of gout flares-co-administration of colchicine in patients on ritonavir:

0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment the following dosage adjustments should be considered:
For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
rifabutin
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial:
rifampin
↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic:
quinine
↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.
β-Blockers:
metoprolol, timolol
↑ Beta-Blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator:
theophylline
↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil
↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor:
atorvastatin
rosuvastatin

↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants:
cyclosporine, tacrolimus, sirolimus (rapamycin)
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Inhaled or Intranasal Steroid e.g.:
Fluticasone
Budesonide
↑ glucocorticoids Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone
fentanyl
↓ methadone
↑ fentanyl
Dosage increase of methadone may be considered.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Neuroleptics:
perphenazine, risperidone, thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol
↓ ethinyl estradiol Alternate methods of contraception should be considered.
PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see Contraindications (4)].
The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir:

Co-administration of ADCIRCA in patients on ritonavir:

In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:

Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.
Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem
↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam
↑ midazolam Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids (systemic) e.g.: budesonide, dexamethasone, prednisone ↑ glucocorticoids Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Stimulant:
methamphetamine
↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
 Concomitant Drug  CmaxSS (Peak plasma concentration)  AUCss(0-12h) (Extent of systemic exposure)
  Erythromycin (500 mg every 8 hrs)   +82%   +109%
  Ketoconazole (400 mg once daily)   +135%   +164%


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin   colchicine ranitidine
tobramycin Antifungals diclofenac  
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
(e.g.,bezafibrate, fenofibrate)
      methotrexate


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin   amiodarone
verapamil ketoconazole erythromycin   bromocriptine
  voriconazole quinupristin/   colchicine
    dalfopristin   danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 







20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de pointes. Avoid concomitant use. (5.3)
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use. (5.3, 7.2)
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine. (7.1)
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug. (7.2)
Digoxin Increased digoxin plasma concentration. (5.8, 7.1)


Table name:
Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug NameClinical Comment
Anticonvulsant agents:
  phenytoin, phenobarbital, carbamazepine
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
Antihistamines:
  astemizole, terfenadine
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials:
  rifabutin,See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2. rifampin
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors or other coadministered antiviral agents.
Ergot Derivatives:
   dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent:
  cisapride
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products:
  St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
HMG-CoA reductase inhibitors:
  lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
  pimozide
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics:
  alprazolam, midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant
Drug Class:
Drug Name
Effect on Concentration of delavirdine or Concomitant DrugClinical Comment
↑ Indicates increase
↓ Indicates decrease
HIV-Antiviral Agents
Amprenavir↑ AmprenavirAppropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
DidanosineSee CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.↓ Delavirdine
↓ Didanosine
Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least one hour.
Indinavir↑ IndinavirA dose reduction of indinavir to 600 mg tid should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir↑ Lopinavir
↑ Ritonavir
Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
Nelfinavir↑ Nelfinavir
↓ Delavirdine
Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir↑RitonavirAppropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
Saquinavir↑ SaquinavirA dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered. (See CLINICAL PHARMACOLOGY: Table 1.) Appropriate doses with respect to safety, efficacy and pharmacokinetics, have not been established.
Other Agents
Acid blockers:
  antacids

H2Receptor antagonists:
  cimetidine, famotidine,   nizatidine, ranitidine
Proton pump inhibitors:
  omeprazole, lansoprazole
↓ DelavirdineDoses of an antacid and RESCRIPTOR should be separated by at least one hour, because the absorption of delavirdine is reduced when coadministered with antacids.
These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines↑ AmphetaminesUse with caution.
Antidepressant:
trazodone
↑ trazodoneConcomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics:
bepridil
↑ AntiarrhythmicsUse with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenoneCaution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant:
warfarin
↑ WarfarinIt is recommended that INR (international normalized ratio) be monitored.
Anti-infective:
clarithromycin
↑ ClarithromycinWhen coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.For patients with CLCR<30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers:
amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil
↑ Calcium channel blockersCaution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
dexamethasone
↓ DelavirdineUse with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents:
  sildenafil
↑ SildenafilSildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors:
  atorvastatin, cerivastatin, fluvastatin
↑ Atorvastatin
↑ Cerivastatin
↑ Fluvastatin
Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants:
  cyclosporine, tacrolimus, rapamycin
↑ ImmunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid:
Fluticasone
↑ fluticasoneConcomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic:
methadone
↑ MethadoneDosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives:
ethinyl estradiol
↑ Ethinyl estradiolConcentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.


Table name:
Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class:
Specific Drugs
Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
didanosine buffered formulations enteric-coated (EC) capsules
↓ atazanavir
↓ didanosine
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓ atazanavir
↑ tenofovir
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
nevirapine ↓ atazanavir
↑ nevirapine
Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors:
saquinavir (soft gelatin capsules)
↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors:
boceprevir
↓ atazanavir
↓ ritonavir
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended.
telaprevir ↓ telaprevir
↑ atazanavir
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
Other Agents
Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics:
carbamazepine
↓ atazanavir
↑ carbamazepine
Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital ↓ atazanavir
↓ phenytoin
↓ phenobarbital
Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals:
ketoconazole, itraconazole
REYATAZ/ritonavir:
↑ ketoconazole
↑ itraconazole
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
voriconazole REYATAZ/ritonavir in subjects with a functional CYP2C19 allele:
↓ voriconazole
↓ atazanavir
REYATAZ/ritonavir in subjects without a functional CYP2C19 allele:
↑ voriconazole
↓ atazanavir
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the co-administration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ:
Treatment of gout flares:

0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir
↑ bosentan
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ritonavir:
For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan:
Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
                        OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
    In treatment-experienced patients:
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol
↑ norgestimatec




↑ ethinyl estradiol
↑ norethindroned
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
     Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
     Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
  REYATAZ/ritonavir
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine
↑ norbuprenorphine
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].


The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:


Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.


Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
  Use of PDE5 inhibitors for erectile dysfunction:         Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
        Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
    In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
 Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 telaprevir
↓ telaprevir
↓ efavirenz
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED
Coadministered
AED
Concentration
Felbatol®
Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)
*CBZ epoxide

Phenobarbital


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name Clinical Comment
Alpha 1-adrenoreceptor antagonist:
alfuzosin
Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics:
amiodarone, quinidine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products:
St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor:
sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine ↑ nelfinavir
↓ delavirdine
nevirapine ↓ nelfinavir (Cmin)
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir ↑ nelfinavir
↑ indinavir
ritonavir ↑ nelfinavir
saquinavir ↑ saquinavir
Other Agents
Anti-coagulant:
warfarin
warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants: May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine
phenobarbital
↓ nelfinavir
Anti-convulsant: Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin ↓ phenytoin
Anti-depressant: trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout
colchicine
↑ colchicine Treatment of gout flares–
coadministration of colchicine in patients on VIRACEPT:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout-flares–
coadministration of colchicine in patients on VIRACEPT:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)–
coadministration of colchicine in patients on VIRACEPT:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial: It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
Endothelin receptor antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor: Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin ↑ atorvastatin
rosuvastatin ↑ rosuvastatin
Immuno-suppressants: Plasma concentrations may be increased by VIRACEPT.
cyclosporine
tacrolimus
sirolimus
↑ immuno-suppressants
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic:
azithromycin

↑ azithromycin
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic: Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone ↓ methadone
Oral Contraceptive: Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol ↓ ethinyl estradiol
PDE5 Inhibitors:
sildenafil
vardenafil
tadalafil



↑ PDE5 Inhibitors
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:
Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid grapefruit juice 


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
a = Plasma concentration increased 25% in some patients, generally
      those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.
   AED Co-administered   
AED Concentration
Topiramate
   Concentration   
 Phenytoin
NC or 25% increasea
48% decrease
 Carbamazepine (CBZ) 
NC
40% decrease
 CBZ epoxideb
NC
NE
 Valproic acid
11% decrease
14% decrease
 Phenobarbital
NC
NE
 Primidone
NC
NE
 Lamotrigine
   NC at TPM doses up to 400 mg/day   
13% decrease


Table name:
Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor:
 Fosamprenavir
 calcium

↓ amprenavir
Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
 Atazanavir sulfate

↓ atazanavir*
Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime).
Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor:
 Indinavir

↓ indinavir*
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor:
 Lopinavir/ritonavir

↓ lopinavir*
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor:
 Ritonavir

↑ ritonavir*
↑ efavirenz*
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor:
 Saquinavir

↓ saquinavir*
Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI:
 Other NNRTIs
↑ or ↓ efavirenz
and/or NNRTI
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist:
 Maraviroc

↓ maraviroc*
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor:
 Raltegravir

↓ raltegravir*
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 Boceprevir

↓ boceprevir*
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 Telaprevir

↓ telaprevir*
↓ efavirenz*
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
 Warfarin

↑ or ↓ warfarin
Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants:
 Carbamazepine

↓ carbamazepine*
↓ efavirenz*

There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
 Phenytoin
 Phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
 Bupropion

↓ bupropion*

The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
 Sertraline ↓ sertraline* Increases in sertraline dosage should be guided by clinical response.
Antifungals:
 Voriconazole

↓ voriconazole*
↑ efavirenz*

SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3 , Tables 8 and 9) .]

 Itraconazole

↓ itraconazole*
↓ hydroxyitraconazole*

Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
 Ketoconazole ↓ ketoconazole Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
 Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
 Clarithromycin

↓ clarithromycin*
↑ 14-OH metabolite*
Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials:
 Rifabutin

↓ rifabutin*
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
 Rifampin ↓ efavirenz* If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers:
 Diltiazem

↓ diltiazem*
↓ desacetyl diltiazem*
↓ N-monodesmethyl diltiazem*
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)
↓ calcium channel blocker
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  Atorvastatin
  Pravastatin
  Simvastatin


  ↓ atorvastatin*
↓ pravastatin*
↓ simvastatin*
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral
 Ethinyl estradiol/
 Norgestimate

↓ active metabolites
of norgestimate*

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant
 Etonogestrel

↓ etonogestrel

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A

↓ immunosuppressant
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic:
 Methadone

↓ methadone*
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Diluent Storage
Room Temp.
(25°C)
Refrigerated
(4°C)
Sterile Water 2 days 10 days
0.9% Sodium Chloride Solution 2 days 10 days
5% Dextrose Solution 2 days 10 days
10% Dextrose Solution 2 days 10 days
5% Dextrose + 0.9% Sodium Chloride Solution* 2 days Incompatible
5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible
* Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazaepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%
↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold
? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
blood dyscrasias —    diarrhea      hyperthyroidism
   see  CONTRAINDICATIONS  elevated temperature   poor nutritional state    
cancer  hepatic disorders   steatorrhea
collagen vascular disease     infectious hepatitis   vitamin K deficiency
congestive heart failure     jaundice


Table name:
Classes of Drug    
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
   5-lipoxygenase Inhibitor    Antiplatelet Drugs/Effects    Leukotriene Receptor Antagonist
   Adrenergic Stimulants, Central    Antithyroid Drugs    Monoamine Oxidase Inhibitors
   Alcohol Abuse Reduction    Beta-Adrenergic Blockers    Narcotics, prolonged
       Preparations    Cholelitholytic Agents    Nonsteroidal Anti-
   Analgesics    Diabetes Agents, Oral          Inflammatory Agents
   Anesthetics, Inhalation    Diuretics    Proton Pump Inhibitors
   Antiandrogen    Fungal Medications,     Psychostimulants
   Antiarrhythmics        Intravaginal, Systemic    Pyrazolones
   Antibiotics    Gastric Acidity and Peptic    Salicylates
      Aminoglycosides (oral)        Ulcer Agents    Selective Serotonin
      Cephalosporins, parenteral    Gastrointestinal          Reuptake Inhibitors
      Macrolides        Prokinetic Agents    Steroids, Adrenocortical
      Miscellaneous        Ulcerative Colitis Agents    Steroids, Anabolic (17-Alkyl
      Penicillins, intravenous,    Gout Treatment Agents           Testosterone Derivatives)
         high dose    Hemorrheologic Agents    Thrombolytics
      Quinolones (fluoroquinolones)    Hepatotoxic Drugs    Thyroid Drugs
      Sulfonamides, long acting    Hyperglycemic Agents    Tuberculosis Agents
      Tetracyclines    Hypertensive Emergency  Agents              Uricosuric Agents
   Anticoagulants    Hypnotics    Vaccines
   Anticonvulsants    Hypolipidemics    Vitamins
   Antidepressants       Bile Acid-Binding Resins
   Antimalarial Agents       Fibric Acid Derivatives
   Antineoplastics          HMG-CoA Reductase   Inhibitors
   Antiparasitic/Antimicrobials
Specific Drugs Reported    
   acetaminophen    fenoprofen    paroxetine
   alcoholIncreased and decreased PT/INR responses have been reported.    fluconazole    penicillin G, intravenous
   allopurinol    fluorouracil    pentoxifylline
   aminosalicylic acid    fluoxetine    phenylbutazone
   amiodarone HCl    flutamide    phenytoin
   argatroban    fluvastatin    piperacillin
   aspirin    fluvoxamine    piroxicam
   atenolol    gefitinib    pravastatin
   atorvastatin    gemfibrozil    prednisone
   azithromycin    glucagon    propafenone
   bivalirudin    halothane    propoxyphene
   capecitabine    heparin    propranolol
   cefamandole    ibuprofen    propylthiouracil
   cefazolin    ifosfamide    quinidine
   cefoperazone    indomethacin    quinine
   cefotetan    influenza virus vaccine    rabeprazole
   cefoxitin    itraconazole    ranitidine
   ceftriaxone    ketoprofen    rofecoxib
   celecoxib    ketorolac    sertraline
   cerivastatin    lansoprazole    simvastatin
   chenodiol    lepirudin    stanozolol
   chloramphenicol    levamisole    streptokinase
   chloral hydrate    levofloxacin    sulfamethizole
   chlorpropamide    levothyroxine    sulfamethoxazole
   cholestyramine    liothyronine    sulfinpyrazone
   cimetidine    lovastatin    sulfisoxazole
   ciprofloxacin    mefenamic acid    sulindac
   cisapride    methimazole    tamoxifen
   clarithromycin    methyldopa    tetracycline
   clofibrate    methylphenidate    thyroid
   warfarin sodium overdose    methylsalicylate ointment (topical)    ticarcillin
   cyclophosphamide    metronidazole    ticlopidine
   danazol    miconazole     tissue plasminogen
   dextran    (intravaginal, oral, systemic)    activator (t-PA)
   dextrothyroxine    moricizine hydrochloride    tolbutamide
   diazoxide    nalidixic acid    tramadol
   diclofenac    naproxen    trimethoprim/sulfamethoxazole
   dicumarol    neomycin    urokinase
   diflunisal    norfloxacin    valdecoxib
   disulfiram    ofloxacin    valproate
   doxycycline    olsalazine    vitamin E
   erythromycin    omeprazole    zafirlukast
   esomeprazole    oxandrolone    zileuton
   ethacrynic acid    oxaprozin
   ezetimibe    oxymetholone
   fenofibrate    pantoprazole


Table name:
edema hypothyroidism 
hereditary coumarin resistance nephrotic syndrome
hyperlipemia


Table name:
Classes of Drugs    
also: diet high in vitamin K unreliable PT/INR determinations
   Adrenal Cortical Steroid Inhibitors     Antipsychotic Medications    Hypolipidemics
   Antacids    Antithyroid Drugs    Bile Acid-Binding Resins
   Antianxiety Agents
   Antiarrhythmics
   Barbiturates
   Diuretics
   HMG-CoA Reductase Inhibitors
   Anticonvulsants    Enteral Nutritional Supplements     Immunosuppressives
   Antidepressants    Fungal Medications, Systemic    Oral Contraceptives,
   Antihistamines    Gastric Acidity and Peptic  Ulcer Agents    Estrogen Containing
   Antineoplastics    Hypnotics    Selective Estrogen Receptor Modulators
   Steroids, Adrenocortical
   Tuberculosis Agents
   Vitamins
Specific Drugs Reported:    
   alcoholIncreased and decreased PT/INR responses have been reported.    warfarin sodium underdosage    phenytoin
   aminoglutethimide    cyclophosphamide    pravastatin
   amobarbital    dicloxacillin    prednisone
   atorvastatin    ethchlorvynol    primidone
   azathioprine    glutethimide    propylthiouracil
   butabarbital    griseofulvin    raloxifene
   butalbital    haloperidol    ranitidine
   carbamazepine    meprobamate    rifampin
   chloral hydrate    6-mercaptopurine    secobarbital
   chlordiazepoxide    methimazole    spironolactone
   chlorthalidone    moricizine hydrochloride    sucralfate
   cholestyramine    nafcillin    trazodone
   clozapine    paraldehyde    vitamin C (high dose)
   corticotropin    pentobarbital    vitamin K
   cortisone    phenobarbital


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaledmebendazole
amoxicillinmedroxyprogesterone
ampicillin, with or without sulbactammethylprednisolone
atenololmetronidazole
azithromycinmetoprolol
caffeine, dietary ingestionnadolol
cefaclornifedipine
co-trimoxazole (trimethoprim andnizatidine
sulfamethoxazole)norfloxacin
diltiazemofloxacin
dirithromycinomeprazole
enflurane prednisone,prednisolone
famotidineranitidine
felodipinerifabutin
finasterideroxithromycin
hydrocortisonesorbitol (purgative doses do not inhibit
isofluranetheophylline absorption)
isoniazidsucralfate
isradipineterbutaline, systemic
influenza vaccineterfenadine
ketoconazoletetracycline
lomefloxacintocainide


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.


Table name:
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
AED Co-administration AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table II. Clinically significant drug interactions with theophylline.*
Drug Type of Interaction Effect†
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may berequired to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours 30% increase
Allopurinol Decreases theophylline clearance at allopurinoldoses  600 mg/day 25% increase
Aminoglutethimide Increases theophylline clearance by induction ofmicrosomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibitingcytochrome P450 1A2 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors. Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression.
Disulfiram Decreases theophylline clearance by inhibitinghydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea,nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount.
Estrogen Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines. Increased risk of ventriculararrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizurethreshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX,higher dose MTX may have a greatereffect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% increase
Pancuronium Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition. Larger dose of pancuronium may berequired to achieve neuromuscularblockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks ofconcurrent PB.
Phenytoin Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity. Serum theophylline and phenytoinconcentrations decrease about 40%.
Propafenone Decreases theophylline clearance andpharmacologic interaction. 40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologicinteraction. 100% increase Beta-2 blocking effectmay decrease efficacy of theophylline
Rifampin Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renalclearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending ontroleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
dietary digestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Antibiotics
ciprofloxacin
gentamicin
tobramycin
trimethoprim with sulfamethoxazole
vancomycin
Antineoplastic
melphalan
 
 
 
Antifungals
amphotericin B
ketoconazole
Anti-Inflammatory Drugs
azapropazon
colchicine
diclofenac
naproxen
sulindac
Gastrointestinal Agents
cimetidine
ranitidine
 
 
Immunosuppressives
tacrolimus
 
Other Drugs
fibric acid derivatives
  (e.g., bezafibrate, fenofibrate)


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
voriconazole quinupristin/dalfopristin colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan terbinafine
rifampin oxcarbazepine octreotide ticlopidine
phenobarbital orlistat St. John's Wort
phenytoin sulfinpyrazone


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole,
posaconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, nefazodone,
gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products
including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet
formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time,
INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum and Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport  - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5’-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum and Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport  - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5’-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments
ANTIVIRALS
Amprenavir 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax No significant change in kinetics. A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine ND Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine No significant change in kinetics. No significant change in kinetics at steady state.
Fosamprenavir/ritonavir 64% ↑ AUC - Drug plus active metabolite 35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir 204% ↑ in AUC 32%↓ in AUC
Lopinavir/ritonavir 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax No significant change in lopinavir kinetics. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir ND 40% ↓ in AUC
Ritonavir 4 fold increase in AUC, 2.5 fold increase in Cmax ND In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133] 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax No significant change in tipranavir kinetics. Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine No significant change in kinetics. Approximately 32%↓ in Cmax and AUC A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS 82% ↑ in AUC No significant change in steady-state plasma concentrations
Itraconazole ND 70% to 75% ↓ in Cmax and AUC One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole 31%↑ Cmax, 72%↑ AUC 43%↓ Cmax, 49%↓ AUC If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole 195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone ND Approximately 27% to 40% ↓ in AUC Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim No significant change in Cmax and AUC Approximately 15% to 20% ↓ in AUC In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin No PK interaction No PK interaction
Clarithromycin Approximately 77% ↑ in AUC Approximately 50%↓ in AUC Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol ND No significant change in AUC or Cmax
Isoniazid ND Pharmacokinetics not affected
Pyrazinamide ND ND Study data being evaluated.
OTHER
Methadone ND No significant effect No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol ND 35%↓ AUC
20%↓ Cmax
Patients should be advised to use other methods of contraception.
Norethindrone ND 46%↓ AUC Patients should be advised to use other methods of contraception.
Tacrolimus ND ND Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline ND No significant change in AUC or Cmax compared with baseline.


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase carbamazepine epoxide levels.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table IV. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled lomefloxacin
mebendazole
amoxicillin medroxyprogesterone
ampicillin, with or without sulbactam methylprednisolone
metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine, dietary ingestion nifedipine
nizatidine
cefaclor norfloxacin
co-trimoxazole
(trimethoprim and sulfamethoxazole)
ofloxacin
omeprazole
prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol (purgative doses do not inhibit theophylline absorption)
felodipine
finasteride
hydrocortisone
insoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Digoxin concentrations increased greater than 50%
     Digoxin Serum     
Concentration
Increase
     Digoxin AUC     
Increase
Recommendations
Quinidine NA 54-83% Measure serum digoxin concentrations before     
initiating concomitant drugs. Reduce digoxin
concentrations by decreasing dose by
approximately 30-50% or by modifying the
dosing frequency and continue monitoring.
Ritonavir NA 86%
Digoxin concentrations increased less than 50%
Amiodarone 17% 40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone 28% 29%
Quinine NA 34-38%
Spironolactone      NA 44%
Verapamil NA 24%
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs
that were studied but reported no significant changes
on digoxin exposure.
No additional actions are required.


Table name:
Drugs that Affect Renal          
Function
A decline in GFR or tubular secretion, as from ACE inhibitors,          
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs
[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone
Analog
Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking
Agents
Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers
and calcium channel
blockers
Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose 18-30 years 31-65 years
No fentanyl 6.4 ± 0.0 6.3 ± 0.4
3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%)
6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%)
No midazolam 6.9 ± 0.1 5.9 ± 0.6
25 µg/kg midazolam - 4.9 ± 0.9 (16%)
50 µg/kg midazolam - 4.9 ± 0.5 (17%)


Table name:
Table 4
Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade
Desflurane Concentration Mean ED95 (µg/kg)
Pancuronium Atracurium Succinylcholine Vecuronium
0.65 MAC 60% N2O/O2 26 123 - -
1.25 MAC 60% N2O/O2 18 91 - -
1.25 MAC O2 22 120 362 19


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents.
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓ lamotrigine    
↓ levonorgestrel
Decreased lamotrigine levels approximately 50%.   Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine   

? CBZ epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine   

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.  
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.


Table name:
Interacting Drug Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine  Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin  Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents  Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 7:  Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine Dose  
(mg/day)
Influence of
Oxcarbazepine on Concentration
(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 10: Pharmacokinetic Interaction Data for Fosaprepitant/Aprepitant and Coadministered Midazolam
Dose of fosaprepitant/ aprepitant Dose of Midazolam Observed Drug Interactions
fosaprepitant 150 mg on Day 1 oral 2 mg on Days 1 and 4 AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4
fosaprepitant 100 mg on Day 1 oral 2 mg oral midazolam AUC ↑ 1.6-fold
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5 oral 2 mg SD on Days 1 and 5 oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3 intravenous 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8 and 15 intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15
oral aprepitant 125 mg intravenous 2 mg given 1 hour after aprepitant intravenous midazolam AUC ↑ 1.5-fold


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered.  Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications.  An alternative or additional method of contraception is recommended.
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir

↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients.

A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin   ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/ritonavir The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Potential Drug Interactions: 
   
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Table 3: Summary of AED interactions with Topiramate
AED
Co-administered
AED
Concentration
Topiramate
Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM – Topiramate
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4 ) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug cyclosporinec, glimepiridea, glipizidea, glyburidea, levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug metformin extended release (ER)d
Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL phenytoina, warfarinb
Drugs that do not interact with colesevelam based on in vitro or in vivo testing aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb


Table name:
Table 3: Summary of AED interactions with Topiramate
AED
Co-administered
AED
Concentration
Topiramate
Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM – Topiramate
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the oral solution formulation is taken within 2 hours of these products (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Table 5: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir ↑ didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity.
methadone ↓ didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX EC.
tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX EC to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 6: Predicted Drug Interactions with VIDEX EC
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [see Warnings and Precautions (5.1) ].
b [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a
Neurotoxic drugs ↑ risk of neuropathy Use with caution.b


Table name:
Table IIl Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
  * Refer to PRECAUTIONS, Drug Interactions for information regarding table.

 albuterol, systemic and inhaled  hydrocortisone  nizatidine
 amoxicillin  isoflurane  norfloxacin
 ampicillin, with or without sulbactam  isoniazid  ofloxacin
 atenolol  isradipine  omeprazole
 azithromycin  influenza vaccine  prednisone, prednisolone
 caffeine, dietary ingestion  ketoconazole  ranitidine
 cefaclor  lomefloxacin  rifabutin
 co-trimoxazole  mebendazole  roxithromycin
 (trimethoprim and sulfamethoxazole) diltiazem  medroxyprogesterone  sorbitol
 dirithromycin  methylprednisolone  (purgative doses do not inhibit theophylline absorption)
 enflurane  metronidazole  sucralfate
 famotidine  metoprolol  terbutaline, systemic
 felodipine  nadolol  terfenadine
 finasteride  nifedipine  tetracycline
tocainide


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting  Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem
Do not exceed 10 mg simvastatin daily 
Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Table 7  Summary of AED Interactions with Trileptal
AED
Coadministered
Dose of AED
(mg/day)
Trileptal Dose
(mg/day)
Influence of
Trileptal on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 10 and 11]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-Antiviral Agents: CCR5 co-receptor antagonists
Maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine   
   Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)   
   Warfarin
   Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.2, 4, 5.2, 7.1, 7.2, 7.3, 7.4, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,
itraconazole,
ketoconazole,
posaconazole,
erythromycin,
clarithromycin,
telithromycin, HIV protease inhibitors,
boceprevir,
telaprevir,
nefazodone),
gemfibrozil, cyclosporine,
danazol,
verapamil, diltiazem
Contraindicated with SIMCOR
Amiodarone, amlodipine, ranolazine Do not exceed 1000/20 mg SIMCOR daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
DRUGS EFFECT
Aspirin w/anti-inflammatory agents Increased
ulcerogenic effects.
Butalbital w/coumarin anticoagulants Decreased effect of
anticoagulant
because of
increased
metabolism
resulting from
enzyme induction.
Butalbital w/tricyclic antidepressants Decreased blood
levels of the
antidepressant.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on concentration of Nevirapine or Concomitant drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol andNorethindrone ↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir ↓Amprenavir
↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓Amprenavir
↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8   Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir /Ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class Examples of Drugs
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine
Dose
(mg/day)
Influence of
Oxcarbazepine on
AED
Concentration
(Mean Change,
90% Confidence
Interval)
Influence of
AED on MHD
Concentration
(Mean Change,
90% Confidence
Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
    [CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase 25% decrease
      [CI: 2% increase,
24% increase]
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800 nc , Pediatrics 30% decrease
    >1200-2400 up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 3% decrease,
48% decrease]
      [CI: 12% increase,
60% increase]
 
Valproic acid 400-2800 600-1800 nc 18% decrease
        [CI: 13% decrease,
40% decrease]


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
CONCOMITANT  DRUG CLINICAL EFFECT(S)        
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%
Valproate ↑lamotrigine Increased lamotrigine concentrations slightly more than 2-fold
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease [Cl: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [Cl: 2% increase, 24% increase] 25% decrease [Cl: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc1,2 up to 40% increase3 [Cl: 12% increase, 60% increase] 30% decrease [Cl: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease [Cl: 13% decrease, 40% decrease]
1nc denotes a mean change of less than 10% 2Pediatrics 3Mean increase in adults at high oxcarbazepine doses


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)  Do not exceed 40 mg atorvastatin daily


Table name:
Table 4 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
Antacids:

  antacids
  (e.g., aluminium, magnesium hydroxide, or calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)

↓ rilpivirine (concomitant intake)
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents:

  fluconazole
  itraconazole
  ketoconazole
  posaconazole
  voriconazole
↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
↓ ketoconazole ,
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H2-Receptor Antagonists:

  cimetidine
  famotidine
  nizatidine
  ranitidine
↔ rilpivirine ,
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)

↓ rilpivirine ,
(famotidine taken 2 hours before rilpivirine)
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics:

  clarithromycin
  erythromycin
  telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:

  methadone
↓ R(–) methadone
↓ S(+) methadone
↔ rilpivirine
↔ methadone (when used with tenofovir)
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓Amprenavir

↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓Amprenavir

↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily.

Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin   ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Potential Drug Interactions:
   
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkanizing Agents Decreased plasma salicylate levels.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased T3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone, ketone bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin
NA - Not Available * - 90% Confidence interval not reported Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo.
Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Atorvastatin 10 mg/day x 8 days 500 mg/day PO on days 6 to 8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25)
Carbamazepine 200 mg/day x 2 days, then 200 mg BID x 18 days 500 mg/day PO for days 16 to 18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06)
Cetirizine 20 mg/day x 11 days 500 mg PO on day 7, then 250 mg/day on days 8 to 11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13)
Didanosine 200 mg PO BID x 21 days 1,200 mg/day PO on days 8 to 21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57)
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.04* 0.95*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05)
Indinavir 800 mg TID x 5 days 1,200 mg PO on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00)
Midazolam 15 mg PO on day 3 500 mg/day PO x 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2 to 10 6 See footnote below NA
Sildenafil 100 mg on days 1 and 4 500 mg/day PO x 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12)
Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg PO on day 7, 250 mg/day on days 8 to 11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22)
Theophylline 300 mg PO BID x 15 days 500 mg PO on day 6, then 250 mg/day on days 7 to 10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31)
Triazolam 0.125 mg on day 2 500 mg PO on day 1, then 250 mg/day on day 2 12 1.06* 1.02*
Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day PO x 7 days 1,200 mg PO on day 7 12 0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03)
Zidovudine 500 mg/day PO x 21 days 600 mg/day PO x 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70)
Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43)


Table name:
Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs (see PRECAUTIONS, Drug Interactions).
NA – Not available * - 90% Confidence interval not reported Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
Coadministered Drug   Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.22 (1.04 to 1.42) 0.92*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2 to 10 6 See footnote below NA


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists GlucocorticoidsOctreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) SulfonamidesTolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate OrlistatSucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil MitotaneTamoxifen Androgens / Anabolic Steroids Asparaginase GlucocorticoidsSlow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - PhenylbutazoneSalicylates ( > 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3    metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins PhenobarbitalRifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4   5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day)Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives- Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline)- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones- Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2 Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem- Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators- (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use)Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered
Drug
Dosing Schedule Effect on Active Moiety
(Risperidone + 9-
Hydroxy-Risperidone
(RatioChange relative to reference)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone AUC Cmax
Enzyme
(CYP2D6)
Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg
twice daily
1.4 1.5 Reevaluate
dosing. Do not
exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Reevaluate
dosing. Do not
exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme
(CYP3A/PgP
inducers)
Inducers
Carbamazepine 573 ± 168
mg/day
3 mg twice
daily
0.51 0.55 Titrate dose
upwards. Do not
exceed twice the
patient’s usual
dose
Enzyme
(CYP3A)
Inhibitors
Ranitidine 150 mg twice
daily
1 mg single
dose
1.2 1.4 Dose adjustment
not needed
Cimetidine 400 mg twice
daily
1 mg single
dose
1.1 1.3 Dose adjustment
not needed
Erythromycin 500 mg 4 times
daily
1 mg single
dose
1.1 0.94 Dose adjustment
not needed
Other Drugs
Amitriptyline 50 mg twice
daily
3 mg twice
daily
1.2 1.1 Dose adjustment
not needed


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Drugs That May Potentiate Renal Dysfunction
Antibiotics Antineoplastics Anti-Inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin colchicine ranitidine
tobramycin Antifungals diclofenac
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim ketoconazole sulindac tacrolimus
with
sulfamethoxazole Other Drugs
fibric acid derivatives
(e.g., bezafibrate,
fenofibrate)


Table name:
Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by Itraconazole1
Drug plasma concentration increased by itraconazole
Antiarrhythmics digoxin, dofetilide2, quinidine2, disopyramide
Anticonvulsants carbamazepine
Antimycobacterials rifabutin
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide2
Benzodiazepines alprazolam, diazepam, midazolam,2, 3 triazolam2
Calcium Channel Blockers dihydropyridines (including felodipine2 and nisoldipine2), verapamil
Gastrointestinal Motility Agents cisapride2
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin2, simvastatin2
Immunosuppressants cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics
Protease Inhibitors indinavir, ritonavir, saquinavir
Other methadone2, levacetylmethadol (levomethadyl) 2, ergot alkaloids2, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl
Decrease plasma concentration of itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors nevirapine
Increase plasma concentration of itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Protease Inhibitors indinavir, ritonavir


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz*
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine
↔ etravirine
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials:
artemether/lumefantrine
↔ etravirine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals:
telaprevir
↔ etravirine
↓ telaprevir
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®.
HMG-CoA
Reductase Inhibitors:
atorvastatin

fluvastatin,
lovastatin,
pitavastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↑ pitavastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone,
methadone
↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
tadalafil,
vardenafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol

Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Grapefruit juice
Avoid grapefruit juice


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
Table 3: Summary of AED Interactions with Topiramate
 AED
Coadministered
 AED
Concentration
 Topiramate
Concentration
 Phenytoin  NC or 25% increasea  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideb  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  15% increase
 


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
Antiretroviral agents
Protease inhibitor:
  atazanavir
↓atazanavir concentration
↑ tenofovir concentration
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir concentration
↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir concentration
↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc concentration Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant concentration
↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion concentration The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole concentration
↓ hydroxy-itraconazole concentration
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole concentration Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole concentration Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin concentration
↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  rifampin
↓ efavirenz concentration If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem concentration
↓ desacetyl diltiazem concentration
↓ N-monodes-methyl diltiazem concentration
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin concentration
↓ pravastatin concentration
↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled diltiazem medroxyprogesterone roxithromycin
dirithromycin methylprednisolone Sorbitol
(purgative doses do  not inhibit theophylline absorption)
amoxicillin enflurane metronidazole
ampicillin, with or without sulbactam famotidine metoprolol
felodipine nadolol
finasteride nifedipine
atenolol hydrocortisone nizatidine sucralfate
azithromycin isoflurane norfloxacin terbutaline, systemic
caffeine, dietary   ingestion isoniazid ofloxacin terfenadine
isradipine omeprazole tetracycline
cefaclor influenza vaccine prednisone,
prednisolone
tocainide
co-trimoxazole (trimethoprim and sulfamethoxazole) ketoconazole
lomefloxacin ranitidine
mebendazole rifabutin
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*


Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine

↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.


No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*



Delavirdine
Etravirine
Rilpivirine
↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin* 




Rifabutin*





Rifampin*
↓ Clarithromycin
↑ 14-OH clarithromycin 




↑ Rifabutin





↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.


Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.




Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*


Ketoconazole*



Itraconazole
↑Nevirapine



↓ Ketoconazole



↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.


Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents: Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Antibiotics Antineoplastic Antifungals Anti-Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs
ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives
(e.g., bezafibrate, fenofibrate)
gentamicin ketoconazole colchicine ranitidine methotrexate
tobramycin diclofenac
trimethoprim 
with sulfamethoxazole
naproxen
vancomycin sulindac


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
voriconazole quinupristin/
dalfopristin
colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs /   Dietary Supplements
nafcillin carbamazepine bosentan St. John’s Wort
rifampin oxcarbazepine octreotide 
phenobarbital  orlistat 
phenytoin sulfinpyrazone 
terbinafine 
ticlopidine


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*



Fosamprenavir/Ritonavir*
↓ Amprenavir

↑ Nevirapine

↓ Amprenavir

↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.

No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*



Delavirdine
Etravirine
Rilpivirine



↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.



Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.






Other Agents
Analgesics:
Methadone*



↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*



Rifabutin*



Rifampin*



↓ Clarithromycin
↑ 14-OH clarithromycin



↑ Rifabutin



↓ Nevirapine



Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.



Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*



Ketoconazole*



Itraconazole

↑Nevirapine



↓ Ketoconazole



↓ Itraconazole

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.

Antithrombotics:
Warfarin

Plasma concentrations may be increased.

Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:
Diltiazem, nifedipine, verapamil

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.

Cancer chemotherapy:
Cyclophosphamide

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Ergot alkaloids:
Ergotamine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.

Motility agents:
Cisapride

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Opiate agonists:
Fentanyl

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Oral contraceptives:
Ethinyl estradiol and Norethindrone*

↓ Ethinyl estradiol
↓ Norethindrone

Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.



Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone +
9-Hydroxy-
Risperidone Ratio*)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/
PgP inducers)
Inducers
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient𕢙s usual dose
Enzyme (CYP3A)
Inhibitors
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
 Atazanavir/Ritonavir*
 ↓ Atazanavir
 
 ↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
 Fosamprenavir*
 
 
 
 Fosamprenavir/Ritonavir*
 
 ↓Amprenavir
 ↑Nevirapine
 
 ↓Amprenavir
 ↑Nevirapine
 
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
 
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
 Indinavir*
 
 ↓ Indinavir
 
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
 Lopinavir/Ritonavir*
 
 ↓ Lopinavir
 
Dosing in adult patients:
 
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
 
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 Nelfinavir*
 ↓Nelfinavir M8 Metabolite
 ↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
 Saquinavir/ritonavir
 The interaction between  nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
 HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
 Efavirenz*
 
 
 Delavirdine
 Etravirine
 Rilpivirine
 ↓Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
 
Plasma concentrations may be altered.
Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
 Other Agents
 Analgesics:
 Methadone*
 ↓Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
 Antiarrhythmics:
 Amiodarone, disopyramide,   lidocaine
 Plasma concentrations  may be decreased.
Appropriate doses for this combination have not been established.
 Antibiotics:
 Clarithromycin*
 
 
 
 
 
 
 
 
 Rifabutin*
 
 
 
 
 
 
 
 Rifampin*
 ↓Clarithromycin
 ↑14-OH clarithromycin
 
 
 
 
 
 
 
 
 ↑Rifabutin
 
 
 
 
 
 
 
 ↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium­intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
 
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
 
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
 Anticonvulsants:
 Carbamazepine,  clonazepam, ethosuximide
 
 Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
 
Use with caution and monitor virologic response and levels of anticonvulsants.
 
 Antifungals:
 Fluconazole*
 
 
 
 
 
 Ketoconazole*
 
 
 
 
 Itraconazole
 ↑Nevirapine
 
 
 
 
 
 
 ↓ Ketoconazole
 
 
 
 
 ↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
 
 
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
 
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
 Antithrombotics:
 Warfarin
 
 Plasma concentrations may be increased.
 
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
 
 Calcium channel blockers:
 Diltiazem, nifedipine,  verapamil
 
 Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
 
 Cancer chemotherapy:
 Cyclophosphamide
 
 Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
 Ergot alkaloids:
 Ergotamine
 
 Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
 Immunosuppressants:  Cyclosporine, tacrolimus,  sirolimus
 Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
 
 Motility agents:
 Cisapride
 
 Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
 Opiate agonists:
 Fentanyl
 
 Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
 Oral contraceptives:
 Ethinyl estradiol and  Norethindrone*
 ↓ Ethinyl estradiol
 ↓ Norethindrone
 
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
 


Table name:
Concomitant Drug
Effect on  Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel

↓ lamotrigine
 
 
 ↓ levonorgestrel

Decreased lamotrigine levels approximately 50%.
 
Decrease in levonorgestrel component by 19%.

Carbamazepine (CBZ)
and CBZ epoxide
↓ lamotrigine

  
 
 ? CBZ epoxide

Addition of carbamazepine decreases lamotrigine concentration approximately 40% 
 
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate

↑ lamotrigine
 
 
 ? valproate

Increased lamotrigine concentrations slightly more than 2-fold.
 
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Drug or Drug Class
Dopamine / Dopamine Agonists Glucocorticoids Octreotide
Effect - Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥1 μg/kg/min); Glucocorticoids (hydrocortisone≥100 mg/day or equivalent); Octreotide ( >100 μg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Drug or Drug Class
Aminoglutethimide
Amiodarone
Iodide
(including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Effect - Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Drug or Drug Class
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Effect - Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Drug or Drug Class
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Sucralfate
Effect - Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may decrease serum TBG concentration
Androgens / Anabolic Steroids Glucocorticoids
Asparaginase Slow Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Drug or Drug Class
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Effect - Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Drug or Drug Class
Carbamazepine Hydantoins Phenobarbital Rifampin
Effect - Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Drug or Drug Class
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥4 mg/day)
Propylthiouracil (PTU)
Effect - Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Drug or Drug Class
Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives
Effect - Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Drug or Drug Class
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Effect - Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Drug or Drug Class
Antidiabetic Agents
- Biguanides
- Meglitinides
- Thiazolidinediones
- Sulfonylureas
- Insulin
Effect - Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Drug or Drug Class
Cardiac Glycosides
Effect - Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Drug or Drug Class
Cytokines - Interferon-α - Interleukin-2
Effect - Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Drug or Drug Class
Growth Hormones - Somatrem - Somatropin
Effect - Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Drug or Drug Class
Ketamine
Effect - Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Drug or Drug Class
Methylxanthine Bronchodilators - (e.g., Theophylline)
Effect - Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Drug or Drug Class
Radiographic Agents
Effect - Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Drug or Drug Class
Sympathomimetics
Effect - Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Drug or Drug Class
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol
(excessive topical use)
Thiazide Diuretics
Effect - These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*
↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*
↓ Amprenavir
 
↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*
↓ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*
↓Lopinavir
Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*
↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy, has not been established.
Saquinavir/Ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
 
↓ Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
 
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:
Methadone*
↓ Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*  
 
 ↓ Clarithromycin
 ↑ 14-OH clarithromycin
 
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*
↑Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*
↓ Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
Use with caution and monitor virologic response and levels of anticonvulsants.
 
Antifungals:
Fluconazole*          
 ↑ Nevirapine
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*
↓ Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
↓ Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased.
 
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
 
Cancer chemotherapy: Cyclophosphamide
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Ergot alkaloids: Ergotamine
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Motility agents: Cisapride
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Opiate agonists: Fentanyl
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*
 
↓ Ethinyl estradiol
↓ Norethindrone
 
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4: Summary of AED Interactions with Topiramate
 AED
Coadministered
 AED
Concentration
 Topiramate
Concentration
 Phenytoin  NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideIs not administered but is an active metabolite of carbamazepine  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  15% increase
 NC = Less than 10% change in plasma concentration
AED = Antiepileptic drug
NE = Not Evaluated
TPM = Topiramate


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release
Drug Effect Clinical Comment
ganciclovir ↑ didanosine  concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release with caution. Monitor for didanosine-associated toxicity.
methadone ↓ didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of dianosine is didanosine delayed-release. Patients should be closely monitored for adequate clinical response when didanosine delayed-release is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction one hour after didanosine Administer nelfinavir one hour after didanosine delayed-release.
tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
     • 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min)
     • 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min
Patients should be monitored for didanosine-associated toxicities and clinical response.
↑ indicates increase
↓ indicates decrease


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release is recommended [see Warnings and Precautions (5.1) ].
Neurotoxic drugs ↑ risk of neuropathy Use with caution. [See Warnings and Precautions (5.6)]
↑ Indicates increase


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)  Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered.  Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications.  An alternative or additional method of contraception is recommended.
Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓ Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twicedaily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin   ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:    
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications.  An alternative or additional method of contraception is recommended.
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir

↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily.

Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Potential Drug Interactions: 
   
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8)
Interacting Agents Prescribing Recommendations
Itraconazole,
ketoconazole,
erythromycin,
clarithromycin,
telithromycin, HIV protease inhibitors,
nefazodone,
fibrates
Avoid VYTORIN
Cyclosporine, danazol Do not exceed 10/10 mg VYTORIN daily
Amiodarone, verapamil Do not exceed 10/20 mg VYTORIN daily
Diltiazem Do not exceed 10/40 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high Oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolismreported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
*    see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] .
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] .
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine

KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)] .
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)] . KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] .

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin

Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR greater then  30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (less then 200 mg/day) or itraconazole (less then 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction] .
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)] . If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole
KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)] .
The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials:
artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↑ lumefantrine
↔ darunavir
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents:
NS3-4A protease inhibitors:

boceprevir
telaprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Coadministered Drug Dosing Schedule Effect on ActiveMoiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*) Risperidone DoseRecommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6)Inhibitors        
Fluoxetine 20 mg/day 2 or 3 mg twicedaily 1.4 1.5 Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Donot exceed 8 mg/day
  20 mg/day 4 mg/day 1.6 -
  40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards.Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four timesdaily 1 mg single dose 1.1 0.94 Dose adjustment not needed
           
Other  Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine
↔ etravirine
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials:
artemether/lumefantrine
↔ etravirine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals:
telaprevir
↔ etravirine
↓ telaprevir
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®.
HMG-CoA
Reductase Inhibitors:
atorvastatin

fluvastatin,
lovastatin,
pitavastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↑ pitavastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone,
methadone
↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
tadalafil,
vardenafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaledlomefloxacin
amoxicillinmebendazole
ampicillin, with or without sulbactammedroxyprogesterone
atenololmethylprednisolone
azithromycinmetronidazole
caffeine, dietary ingestionmetoprolol
cefaclornadolol
co-trimoxazole (trimethoprim and sulfamethoxazole)nifedipine
diltiazemnizatidine
dirithromycinnorfloxacin
enfluraneofloxacin
famotidineomeprazole
felodipineprednisone, prednisolone
finasterideranitidine
hydrocortisonerifabutin
isofluraneroxithromycin
isoniazidsorbitol (purgative doses do not inhibit theophylline absorption)
isradipinesucralfate
influenza vaccineterbutaline, systemic
ketoconazoleterfenadine
tetracycline
tocainide
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs) +82% +109%
Ketoconazole (400 mg once daily) +135% +164%


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-half when used concomitantly (2.6, 7.1), except when used as adjunctive treatment with antidepressants (2.6) CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug concentrations; double ABILIFY dose when used concomitantly (2.6, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.

AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Antibiotics Antineoplastic   Antifungals           Anti-
Inflammatory
Drugs
Gastrointestinal 
Agents
Immunosuppressives     Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin Bketoconazole azapropazoncolchicine diclofenacnaproxen sulindac cimetidine ranitidine tacrolimus fibric acid
derivatives (e.g., bezafibrate, 
fenofibrate)


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs                   
diltiazem fluconazole azithromycin methylprednisolone     allopurinol                           
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
quinupristin/ colchicine
voriconazole dalfopristin danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/DietarySupplements
nafcillin carbamazepine bosentan  St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily,
7 days
800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Phenylephrine:
Drug Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants. Pressor response increased.
Phenylephrine with ergot alkaloids. Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. Synergistic adrenergic response.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration
of Lamotrigine or
Concomitant Drug
 
Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
 
Decreased lamotrigine levels approximately 50%.
 
 
↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
 
? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
  Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
 Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
   ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
   ? CBZ epoxide  May increase CBZ epoxide levels
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2-fold.
   ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
DRUG DESCRIPTION OF INTERACTION 
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased  bleeding.


Table name:
DRUG DESCRIPTION OF INTERACTION 
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkanizing Agents  Decreased plasma salicylate levels.


Table name:
DRUG DESCRIPTION OF INTERACTION 
Heparin   Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.  
Uricosuric Agents  Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
LABORATORY TESTS  EFFECT OF  SALICYLATES 
Thyroid Function Decreased PBI;  increased T3 uptake. 
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone, ketone bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids  False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values. 
Uric acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine
↔ etravirine
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
HMG-CoA
Reductase Inhibitors:
atorvastatin

fluvastatin,
lovastatin,
pitavastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↑ pitavastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone,
methadone
↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
tadalafil,
vardenafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone) (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors    
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day 4 mg/day 1.6 -
  40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
           
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.
Table 5 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration↑ = Increase, ↓ = Decrease, ⇔ = No Effect Clinical Comment
Acid Reducing Agents:
AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)
↓ elvitegravir Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Proton Pump Inhibitors
H2 Receptor Antagonists
⇔ elvitegravir No dose adjustment is needed when STRIBILD is combined with either H2 receptor antagonists or proton pump inhibitors.
Antiarrhythmics:
e.g.
amiodarone
bepridil
digoxin
disopyramide
flecainide
systemic lidocaine mexiletine
propafenone
quinidine
↑ antiarrhythmics
↑ digoxin
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials:
clarithromycin
telithromycin
↑ clarithromycin
↑ telithromycin
↑ cobicistat
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD.
Patients with CLcr greater than or equal to 60 mL/min:
No dose adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/min and 60 mL/min:
The dose of clarithromycin should be reduced by 50%.
Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants:
warfarin
Effect on warfarin unknown Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants:
carbamazepine
oxcarbazepine phenobarbital
phenytoin
↑ carbamazepine
↓ elvitegravir
↓ cobicistat
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.

clonazepam
ethosuximide
↑ clonazepam
↑ ethosuximide
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g.
paroxetine

Tricyclic
Antidepressants (TCAs)
e.g.
amitriptyline
desipramine
imipramine
nortriptyline
buproprion

trazodone
↑ SSRIs
↑ TCAs
↑ trazodone
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended.
Antifungals:
itraconazole ketoconazole
voriconazole
↑ elvitegravir
↑ cobicistat
↑ itraconazole
↑ ketoconazole
↑voriconazole
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout:
colchicine
↑ colchicine
STRIBILD should not be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin
rifapentine
↓ elvitegravir
↓ cobicistat
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers:
e.g.
metoprolol
timolol
↑ beta-blockers Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers:
e.g.
amlodipine
diltiazem
felodipine
nicardipine
nifedipine
verapamil
↑ calcium channel blockers Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid:
Systemic:

dexamethasone
↓ elvitegravir
↓ cobicistat
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid:
Inhaled/Nasal:

fluticasone
↑ fluticasone Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists:
bosentan
↑ bosentan
Coadministration of bosentan in patients on STRIBILD:
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of STRIBILD in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
↑ atorvastatin
Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives:
norgestimate/ethinyl estradiol
↑ norgestimate
↓ ethinyl estradiol
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events.

Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non hormonal) methods of contraception can be considered.
Immuno-suppressants:
e.g.
cyclosporine
sirolimus
tacrolimus
↑ immuno-suppressants Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Inhaled Beta Agonist:
salmeterol
↑ salmeterol Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics:
e.g.
perphenazine
risperidone
thioridazine
↑ neuroleptics A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors:
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD:
Coadministration of tadalafil in patients on STRIBILD:
   
Sedative/hypnotics:
Benzodiazepines:
e.g.
Parenterally administered midazolam
clorazepate
diazepam
estazolam
flurazepam
buspirone
zolpidem
↑ sedatives/hypnotics
Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated.

With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*  Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,felodipinenorfloxacin
   systemic and inhaledfinasterideofloxacin
amoxicillinhydrocortisoneomeprazole
ampicillin,isofluraneprednisone, prednisolone
   with or without sulbactamisoniazidranitidine
atenololisradipinerifabutin
azithromycininfluenza vaccineroxithromycin
caffeine,ketoconazolesorbitol
dietary ingestionlomefloxacin   (purgative doses do not
cefaclormebendazole   inhibit theophylline
co-trimoxazolemedroxyprogesterone   absorption)
   (trimethoprimmethylprednisolonesucralfate
   sulfamethoxazole)metronidazoleterbutaline, systemic
diltiazemmetoprololterfenadine
dirithromycinnadololtetracycline
enfluranenifedipinetocainide
famotidinenizatidine


Table name:
 AED Co-administered  AED Concentration  Topiramate Concentration
 Phenytoin  NC or 25% increasea  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideb  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  13% decrease


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine
Agonists Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone > 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
     
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
     
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
     
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events
and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled diltiazem medroxyprogesterone roxithromycin
dirithromycin methylprednisolone Sorbitol
(purgative doses do  not inhibit theophylline absorption)
amoxicillin enflurane metronidazole
ampicillin, with or without sulbactam famotidine metoprolol
felodipine nadolol
finasteride nifedipine
atenolol hydrocortisone nizatidine sucralfate
azithromycin isoflurane norfloxacin terbutaline, systemic
caffeine, dietary   ingestion isoniazid ofloxacin terfenadine
isradipine omeprazole tetracycline
cefaclor influenza vaccine prednisone,
prednisolone
tocainide
co-trimoxazole (trimethoprim and sulfamethoxazole) ketoconazole
lomefloxacin ranitidine
mebendazole rifabutin
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high Oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 3: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Valuesa
Drug Didanosine Dosage n AUC of Didanosine (90% CI) Cmax of Didanosine (90% CI)
tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 26 ↑ 48%
(31, 67%)
↑ 48%
(25, 76%)
tenofovir,b  300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 25 ↑ 60%
(44, 79%)
↑ 64%
(41, 89%)
tenofovir,b  300 mg once daily with a light mealc 200 mg single dose with tenofovir and a light meal 250 mg single dose with tenogovir and a light meal 325 mg single dose with tenofovir and a light meal 33 33 33 ↑ 16%
(6, 27%)d
↔(-13, 5%)e    ↑ 13% (3, 24%)
↓ 12%
(-25, 3%)d
↓ 20%
(-32, -7%)e
↓ 11%
(-24, 4%)e
↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60kg with creatinine clearance ≥60
mL/min.
b tenofovir disporoxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with didanosine delayed-release capsules 250 mg administered alone under
fasting coniditions.
e Compared with didanosine delayed-release capsules 400 mg administered alone under
fasting conditions.


Table name:
Table 4: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Valuesa
↔ Indicates no change, or mean increase or decrease of less than 10%.
* The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. All studies conducted in healthy volunteers ≥ 60 kg with creatinine clearance ≥ 60 mL/min. Tenofovir disoproxil fumarate. § 373 kcalories, 8.2 grams fat.
    Drug Didanosine Dosage n AUC of Coadministered Drug Cmax of Coadministered Drug
ciprofloxacin,
750 mg single dose
indinavir,
800 mg single dose
ketoconazole,
200 mg single dose
tenofovir,
300 mg once daily
with a light meal§
tenofovir,
300 mg once daily
with a light meal§
400 mg single dose 400 mg single dose 400 mg single dose 400 mg single dose fasting 2h before tenofovir 400 mg single dose with tenofovir anda light meal 16 23 21 25 25


Table name:
Table 5: Results of Drug Interaction Studies with Buggered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine plasma AUC and Cmax Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS, Drug Interactions )
Drug Didanosine Dosage n AUC Didanosine (95% CI) Cmax of Didanosine (95% CI)
allopurinol, Renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232%
healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69%
ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA
methadone, chronic maintenance dose 200 mg single dose 16, 10a ↓57% ↓66%
tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↑44% (31, 59%)d ↔28% (11, 48%)d
No Clinically Significant Interactions Observed
ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8e ↓16% ↓28%
ininavir, 800 mg single dose simultaneous 200 mg single dose 16
1 h before didanosine 200 mg single dose 16 ↓17% (-27, -7%)d ↓13% (-28, 5%)d
ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12e ↓12%
loperamide, 4 mg q6h for 1 day 300 mg single dose 12e ↓23%
metoclopramide, 10 mg single dose 300 mg single dose 12e ↑13%
ranitidine, 150 mg 2 h before didansine 375 mg single dose 12e ↑14% ↑13%
rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8e
trimethoprim, 200 mg single dose 200 mg single dose 8e ↑17% (-23, 77%)
zidovudine, 200 mg q7h for 3 days 200 mg q12h for 3 days 8e
↑ indicates increase
↓ indicates decrease
↔ indicates no change, or mean increase or decrease of <10%.
a Parellel-group design; entries are subjects receiving combination and control regimens, respectively.
b tenogovir disoproxil fumarate
c patients <60 kg with creatinine clearance >60 mL/min.
d 90% CI
e HIV-infected patients
N/A Not available


Table name:
Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
No Clinically Significant Interaction Observed
Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose 200 mg q12h for 14 days 6a
delaviridine, 400 mg single dose simultaneous 125 or 200 mg q12h 12a ↓32%b ↓53%b
1 hr before didanosine 125 or 200 mg q12h 12a ↑20% ↑18%
ganciclovir, 1000 mg q8h, 2h after didanosine 200 mg q12h 12a ↓21% NA
nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12%
ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16%
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↑17%
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%)
tenofovir,C 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days 14
trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%)
↑ indicates increase. ↓indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%.
aHIV-infected patients.
bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules.
ctenofovir disoproxil fumarate.
dpatients <60 kg with creatinine clearance >60 mL/min.
NA Not available


Table name:
 Interacting Agents  Prescribing Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol  Contraindicated with simvastatin 
 Verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine   Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to for information regarding table. PRECAUTIONS, Drug Interactions
albuterol,  systemic and inhaled felodipinefinasteride nizatidinenorfloxacin
amoxicillin hydrocortisone ofloxacin
ampicillin,   with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone
atenolol isradipine ranitidine
azithromycin influenza vaccine rifabutin
caffeine,   dietary ingestion ketoconazo lelomefloxacin roxithromycin sorbitol
cefaclor mebendazole         (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone    inhibit theophylline   absorption)
diltiazem metronidazole sucralfate
dirithromycin metoprolol terbutaline, systemic
enflurane nadolol terfenadine
famotidine nifedipine tetracycline
tocainide


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
  
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%
Valproate ↑lamotrigine Increased lamotrigine concentrations slightly more than 2-fold
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Agents  Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
Gemfibrozil, cyclosporine, danazol  Do not exceed 10 mg simvastatin daily 
Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine
Dose

(mg/day)
Influence of
Oxcarbazepine on AED

Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 4: Summary of AED Interactions with Topiramate
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM = Topiramate
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose 18-30 years 31-65 years
No fentanyl 6.4 ± 0.0 6.3 ± 0.4
3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%)
6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%)
No midazolam 6.9 ± 0.1 5.9 ± 0.6
25 µg/kg midazolam - 4.9 ± 0.9 (16%)
50 µg/kg midazolam - 4.9 ± 0.5 (17%)


Table name:
Table 4
Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade
Desflurane Concentration Mean ED95 (µg/kg)
Pancuronium Atracurium Succinylcholine Vecuronium
0.65 MAC 60% N2O/O2 26 123 - -
1.25 MAC 60% N2O/O2 18 91 - -
1.25 MAC O2 22 120 362 19


Table name:
AED Coadministered
AED Concentration
Topiramate 
Concentration

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents  Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
Gemfibrozil, cyclosporine, danazol  Do not exceed 10 mg simvastatin daily 
Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
blood dyscrasias -
  see CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
  infectious hepatitis
  jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
  Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
  Aminoglycosides (oral)
  Cephalosporins, parenteral
  Macrolides
  Miscellaneous
  Penicillins, intravenous,
    high dose
  Quinolones
    (fluoroquinolones)
  Sulfonamides, long acting
  Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
  Intravaginal, Systemic†
Gastric Acidity and Peptic
  Ulcer Agents†
Gastrointestinal
  Prokinetic Agents
  Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
  Agents
Hypnotics†
Hypolipidemics†
  Bile Acid-Binding Resins†
  Fibric Acid Derivatives
  HMG-CoA Reductase
    Inhibitors†
Leukotriene Receptor
  Antagonist
Monoamine Oxidase
  Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
  Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
  Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
  Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
  dietary deficiencies
  prolonged hot weather
  unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
  ointment (topical)
metronidazole
miconazole
  (intravaginal, oral,
    systemic)
moricizine
  hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
  intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
  activator (t-PA)
tolbutamide
tramadol
trimethoprim/
  sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Classes of Drugs
Adrenal Cortical Steroid
  Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
  Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
  Ulcer Agents†
Hypnotics†
Hypolipidemics†
  Bile Acid-Binding Resins†
  HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
  Containing
Selective Estrogen Receptor
  Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Specific Drugs Reported
also: diet high in vitamin K
        unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs) +82% +109%
Ketoconazole (400 mg once daily) +135% +164%


Table name:
Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials:
artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↑ lumefantrine
↔ darunavir
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents:
NS3-4A protease inhibitors:

boceprevir
telaprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓Amprenavir

↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir

↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz












The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Delavirdine
Etravirine
Rilpivirine



Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.










Other Agents
Analgesics:
Methadone*



↓ Methadone





Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.



Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*



↓ Clarithromycin

↑ 14-OH clarithromycin



Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.



Rifabutin*



↑Rifabutin



Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.



Rifampin*



↓ Nevirapine



Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.



Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide

Plasma concentrations of nevirapine and the anticonvulsant may be decreased.

Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:
Fluconazole*



↑Nevirapine



Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.



Ketoconazole*



↓ Ketoconazole



Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Itraconazole



↓ Itraconazole



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.



Antithrombotics:
Warfarin
Plasma concentrations may be decreased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be increased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
  ↑ rivaroxaban Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.

Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g.
budesonide,
dexamethasone,
prednisone
↓ lopinavir
↑ glucocorticoids
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor:
boceprevir
↓ lopinavir
↓ boceprevir
↓ ritonavir
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor:
telaprevir
↓ telaprevir
↔ lopinavir
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.:
fluticasone,
budesonide
↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase.
↓ Indicates decrease.
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate ↑didanosine concentration A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.
Neurotoxic drugs ↑risk of neuropathy Use with caution.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily, 7 days 800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class:
Drug Name
Effect on
Concentration
Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine ↑ nelfinavir (Cmin)
↓ delavirdine
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine ↓ nelfinavir (Cmin) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir ↑ nelfinavir
↑ indinavir
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir ↑ nelfinavir
↔ ritonavir
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir ↑ nelfinavir
↑ saquinavir
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital
Phenytoin

↓ nelfinavir

↓ phenytoin
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine ↑ colchicines Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity.

Treatment of gout flares –
co- administration of colchicine in patients on VIRACEPT:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout-flares –
coadministration of colchicine in patients on VIRACEPT:


If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan:
Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin
Rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine
Tacrolimus
Sirolimus
↑ immuno-suppressants
↑ nelfinavir
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol ↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin ↑ azithromycin Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone ↓ methadone Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol
Norethindrone
↓ ethinyl estradiol
↓ norethindrone
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil
Vardenafil
Tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

• Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ].

• The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT:

Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:

Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole ↓ nelfinavir Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine
Dose

(mg/day)
Influence of
Oxcarbazepine on AED

Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, erythromycin, clarithromycin, 
   telithromycin, HIV protease inhibitors, nefazodone
   Avoid simvastatin
   Gemfibrozil, cyclosporine, danazol
   Do not exceed 10 mg simvastatin daily
   Amiodarone, verapamil
   Do not exceed 20 mg simvastatin daily
   Diltiazem    Do not exceed 40 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
1A22C93A42C19
WarfarinWarfarinAlprazolamOmeprazole
Theophylline
Propranolol
Tizanidine


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
 Drug  Description of Interaction
 Tolbutamide; Sulfonylureas  Hypoglycemia potentiated
 Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
 Oral Anticoagulants  Increased Bleeding


Table name:
 Drug  Description of Interaction
 Corticosteroids             Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
 Ammonium Sulfate Increases plasma salicylate level 


Table name:
 Drug                              Description of Interaction
 Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin­-treated patients
 Pyrazinamide Inhibits pyrazinamide-­induced hyperuricemia
 Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
 Laboratory Tests      Effects of Salicylates                                                        
 Thyroid Function  Decreased PBI; increased T3 uptake
 Urinary Sugar  False negative with glucose oxidase; false positive with Clinitest with high­dose salicylate  therapy (2­-5 g qd)
 5 Hydroxyindole AceticAcid  False negative with fluorometric test
 Acetone, Ketone Bodies  False positive FeCl3 inGerhardt reaction; red color persists with boiling
 17-­OH Corticosteroids  False reduced values with >4.8 g qd salicylate
 Vanilmandelic Acid  False reduced values
 Uric Acid  May increase or decrease depending on dose
 Prothrombin  Decreased levels; slightly increased prothrombin time


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents
Prescribing Recommendations
Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid 
grapefruit juice 


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Antibiotics Anti-neoplastics Antifungals Anti-inflammatory Drugs Gastrointestinal Agents Immuno-suppressives Other Drugs
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil fluconazole itraconazole ketoconazole voriconazole azithromycin clarithromycin erythromycin quinupristin/ dalfopristin methylprednisolone allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin rifampin carbamazepine oxcarbazepine phenobarbital phenytoin bosentan octreotide orlistat sulfinpyrazone terbinafine ticlopidine St. John’s Wort


Table name:
Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA in Healthy Subjects or Patients with Schizophrenia
 Coadministered drug  Dose schedule  Effect on LATUDA pharmacokinetics  Recommendation
   Coadministered drug  LATUDA  C max  AUC  
 Ketoconazole
(strong CYP3A4 inhibitor)
 400 mg/day
for 5 days
 10 mg
single dose
 6.9-times
LATUDA alone
 9-times
LATUDA alone
 Should not be coadministered with LATUDA
 Diltiazem
(moderate CYP3A4 inhibitor)
 240 mg/ day
for 5 days
 20 mg
single dose
 2.1- times
LATUDA alone
 2.2- times
LATUDA alone
 LATUDA dose should not exceed 40 mg/day if coadministered
 Rifampin
(strong CYP3A4 inducer)
 600 mg/day
for 8 days
 40 mg
single dose
 1/7th of LATUDA alone  1/5th of LATUDA alone  Should not be coadministered with LATUDA
 Lithium
 600 mg BID
for 8 days
 120 mg/day
for 8 days
 0.9-times LATUDA alone  1.1- times LATUDA alone  No LATUDA dose adjustment required.


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drugs That May Potentiate Renal Dysfunction
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole     melphalan   azapropazon colchicine diclofenac naproxen sulindac       cimetidine ranitidine  
Antifungals
amphotericin B ketoconazole   Immunosuppressives
tacrolimus  
Other Drugs
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil   fluconazole itraconazole ketoconazole voriconazole   azithromycin clarithromycin erythromycin quinupristin/ dalfopristin   methylprednisolone   allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives


Table name:
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine 


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
boceprevir No dose adjustment required for ISENTRESS or boceprevir.
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
DRUG INTERACTIONS
CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1) Imipramine: Decreased alertness observed with combination use. (7.1) Chlorpromazine:Impaired alertness and psychomotor performance observed with combination use (7.1) Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2) Ketoconazole: Combination use increases exposure to and effect of zolpidem (7.2)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of
Nevirapine or Concomitant
Drug
Clinical Comment
Atazanavir/Ritonavir
↓ Atazanavir
 
↑ Nevirapine
Do not co-administer nevirapine with atazanavir
because nevirapine substantially decreases
atazanavir exposure.
 
Clarithromycin
 
↓ Clarithromycin
 
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly
decreased by nevirapine; however, 14-OH
metabolite concentrations were increased.
Because clarithromycin active metabolite has
reduced activity against Mycobacterium avium-
intracellulare complex, overall activity against
this pathogen may be altered. Alternatives to
clarithromycin, such as azithromycin, should
be considered.
Efavirenz
↓ Efavirenz
There has been no determination of appropriate
doses for the safe and effective use of this
combination [see
Warnings and Precautions (5.4) ].
 
Ethinyl estradiol and Norethindrone
 
↓ Ethinyl estradiol
 
↓ Norethindrone
Oral contraceptives and other hormonal
methods of birth control should not be used as
the sole method of contraception in women
taking nevirapine, since nevirapine may lower
the plasma levels of these medications. An
alternative or additional method of
contraception is recommended.
 
Fluconazole
 
↑ Nevirapine
Because of the risk of increased exposure to
nevirapine, caution should be used in
concomitant administration, and patients
should be monitored closely for nevirapine
-associated adverse events.
Fosamprenavir
↓Amprenavir
 
 
↑Nevirapine
Co-administration of nevirapine and
fosamprenavir without ritonavir is not
recommended.
 
Fosamprenavir/Ritonavir
↓Amprenavir
 
 
↑Nevirapine
No dosing adjustments are required when
nevirapine is co-administered with 700/100 mg
of fosamprenavir/ritonavir twice daily.
 
 
Indinavir
 
↓ Indinavir
Appropriate doses for this combination are not
established, but an increase in the dosage of
indinavir may be required.
 
Ketoconazole
 
↓ Ketoconazole
Nevirapine and ketoconazole should not be
administered concomitantly because decreases
in ketoconazole plasma concentrations may
reduce the efficacy of the drug.
 
Lopinavir/Ritonavir
 
↓Lopinavir
A dose increase of lopinavir/ritonavir tablets to
500/125 mg twice-daily is recommended when
used in combination with nevirapine.
 
A dose increase of lopinavir/ritonavir oral
solution to 533/133 mg twice daily with food is
recommended in combination with nevirapine.
 
In children 6 months to 12 years of age
receiving lopinavir/ritonavir solution,
consideration should be given to increasing the
dose of lopinavir/ritonavir to 13/3.25 mg/kg for
those 7 to <15 kg; 11/2.75 mg/kg for those 15
to 45 kg; and up to a maximum dose of 533/
133 mg twice daily.
 
Refer to the lopinavir/ritonavir package insert
for complete pediatric dosing instructions when
lopinavir/ritonavir tablets are used in
combination with nevirapine.
 
Methadone
 
↓ Methadone
Methadone levels were decreased; increased
dosages may be required to prevent symptoms
of opiate withdrawal. Methadone-maintained
patients beginning nevirapine therapy should be
monitored for evidence of withdrawal and
methadone dose should be adjusted
accordingly.
 
Nelfinavir
↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin
The appropriate dose for nelfinavir in
combination with nevirapine, with respect to
safety and efficacy, has not been established.
 
Rifabutin
↑ Rifabutin
Rifabutin and its metabolite concentrations
were moderately increased. Due to high
intersubject variability, however, some patients
may experience large increases in rifabutin
exposure and may be at higher risk for rifabutin
toxicity. Therefore, caution should be used in
concomitant administration.
 
Rifampin
 
↓ Nevirapine
Nevirapine and rifampin should not be
administered concomitantly because decreases
in nevirapine plasma concentrations may
reduce the efficacy of the drug. Physicians
needing to treat patients co-infected with
tuberculosis and using a nevirapine-containing
regimen may use rifabutin instead.
 
Saquinavir/Ritonavir
The interaction between
nevirapine and
saquinavir/ritonavir has not
been evaluated
The appropriate doses of the combination of
nevirapine and saquinavir/ritonavir with
respect to safety and efficacy have not been
established.
Potential Drug Interactions:
Drug Class
Examples of Drugs
 
Antiarrhythmics
Amiodarone, disopyramide,
lidocaine
Plasma concentrations may be decreased.
Anticonvulsants
Carbamazepine, clonazepam,
ethosuximide
Plasma concentrations may be decreased.
Antifungals
Itraconazole
Plasma concentrations of some azole
antifungals may be decreased. Nevirapine and
itraconazole should not be administered
concomitantly due to a potentialdecrease in
itraconazole plasma concentrations.
Calcium channel blockers
Diltiazem, nifedipine,
verapamil
Plasma concentrations may be decreased.
Cancer chemotherapy
Cyclophosphamide
Plasma concentrations may be decreased.
Ergot alkaloids
Ergotamine
Plasma concentrations may be decreased.
Immunosuppressants
Cyclosporin, tacrolimus, sirolimus
Plasma concentrations may be decreased.
Motility agents
Cisapride
Plasma concentrations may be decreased.
Opiate agonists
Fentanyl
Plasma concentrations may be decreased.
Antithrombotics
Warfarin
Plasma concentrations may be increased.
Potential effect on anticoagulation. Monitoring
of anticoagulation levels is recommended.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
 ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 ? CBZ epoxide  May increase CBZ epoxide levels.
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2 fold.
 ? valproate  Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
Up to 1 year
Other drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicityfrom methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkanizing Agents Decreased plasma salicylate levels.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased T3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone, ketone bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name Clinical Comment
Alpha 1-adrenoreceptor antagonist:
alfuzosin
Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics:
amiodarone, quinidine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products:
St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor:
sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine ↑ nelfinavir
↓ delavirdine
nevirapine ↓ nelfinavir (Cmin)
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir ↑ nelfinavir
↑ indinavir
ritonavir ↑ nelfinavir
saquinavir ↑ saquinavir
Other Agents
Anti-coagulant:
warfarin
warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants: May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine
phenobarbital
↓ nelfinavir
Anti-convulsant: Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin ↓ phenytoin
Anti-depressant: trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout
colchicine
↑ colchicine Treatment of gout flares–
coadministration of colchicine in patients on VIRACEPT:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout-flares–
coadministration of colchicine in patients on VIRACEPT:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)–
coadministration of colchicine in patients on VIRACEPT:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial: It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
Endothelin receptor antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor: Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin ↑ atorvastatin
rosuvastatin ↑ rosuvastatin
Immuno-suppressants: Plasma concentrations may be increased by VIRACEPT.
cyclosporine
tacrolimus
sirolimus
↑ immuno-suppressants
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic:
azithromycin

↑ azithromycin
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic: Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone ↓ methadone
Oral Contraceptive: Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol ↓ ethinyl estradiol
PDE5 Inhibitors:
sildenafil
vardenafil
tadalafil



↑ PDE5 Inhibitors
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:
Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine  Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin  Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents  Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease,57% decrease]
Phenobarbital 100-150 600-1800 14% increase[CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease,51% decrease]
Phenytoin 250-500 600-1800>1200-2400 nc up to 40% increase [CI: 12% increase,60% increase] 30% decrease [CI: 3% decrease,48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease,40% decrease]


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
   dietary ingestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.


Table name:
Interacting  Drug
Interaction

Multivalent cation-containing products including antacids, metal cation or didanosine


Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 




Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

Antidiabetic agent

Carefully monitor blood glucose (5.11, 7.3)


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3    metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4   5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2 Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine
Dose

(mg/day)
Influence of
Oxcarbazepine on AED

Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin   colchicine ranitidine
tobramycin Antifungals diclofenac  
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
      (e.g.,bezafibrate, fenofibrate)
methotrexate


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin   amiodarone
verapamil ketoconazole erythromycin   bromocriptine
  voriconazole quinupristin/   colchicine
    dalfopristin   danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)  Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort
( hypericum perforatum)
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration of Delavirdine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Amprenavir ↑Amprenavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Didanosinea ↓Delavirdine↓Didanosine Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
Indinavira ↑Indinavir A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir ↑Lopinavir↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavira ↑Nelfinavir↓Delavirdine Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavira ↑Saquinavir A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
Other Agents
Acid blockers: Antacidsa ↓Delavirdine Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines ↑Amphetamines Use with caution.
Antidepressant: Trazodone ↑Trazodone Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics: Bepridil ↑Antiarrhythmics Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin ↑Warfarin It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycina ↑Clarithromycin When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil ↑Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Delavirdine Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil ↑Sildenafil Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin ↑Atorvastatin ↑Cerivastatin↑Fluvastatin Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone ↑Fluticasone Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic: Methadone ↑Methadone Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol ↑Ethinyl estradiol Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,diltiazemmedroxyprogesteroneroxithromycin
   systemic and inhaleddirithromycinmethylprednisolonesorbitol
amoxicillinenfluranemetronidazole   (purgative doses
ampicillin,famotidinemetoprolol   do not inhibit
   with or withoutfelodipinenadolol   theophylline
   sulbactamfinasteridenifedipine   absorption)
atenololhydrocortisonenizatidinesucralfate
azithromycinisofluranenorfloxacinterbutaline, systemic
caffeine,isoniazidofloxacinterfenadine
   dietary ingestionisradipineomeprazoletetracycline
cefaclorinfluenza vaccineprednisone,tocainide
co-trimoxazoleketoconazole   prednisolone
   (trimethoprim andlomefloxacinranitidine
   sulfamethoxazole)mebendazolerifabutin


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants Increased bleeding

II. Drugs changing salicylate levels by altering renal tubular reabsorption:
Drug Description of Interaction
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level

III. Drugs with complicated interactions with salicylates:
Drug Description of Interaction
Heparin Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

The following alterations of laboratory tests have been reported during salicylate therapy6:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd)
5 Hydroxyindole Acetic Acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH Corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With Theophylline*
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine      ↓levonorgestrel Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine ? CBZ epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%.  May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine    ? valproate Increased lamotrigine concentrations slightly more than 2-fold.  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name Clinical Comment
Antiarrhythmics:
amiodarone, quinidine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products:
St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Proton Pump Inhibitors Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
HIV-Antiviral Agents
Protease Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir ↑ nelfinavir
↑ indinavir
ritonavir ↑ nelfinavir
saquinavir ↑ saquinavir
Non-nucleoside Reverse Transcriptase Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine ↑ nelfinavir
↓ delavirdine
nevirapine ↓ nelfinavir (Cmin)
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Other Agents
Anti-Convulsants: May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine
phenobarbital
↓ nelfinavir
Anti-Convulsant: Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin ↓ phenytoin
Anti-Mycobacterial: It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
PDE5 Inhibitors:
sildenafil
vardenafil
tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended.
HMG-CoA Reductase Inhibitor: Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin ↑ atorvastatin
rosuvastatin ↑ rosuvastatin
Immuno-suppressants: Plasma concentrations may be increased by VIRACEPT.
cyclosporine
tacrolimus
sirolimus
↑ immuno-suppressants
Narcotic Analgesic: Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone ↓ methadone
Oral Contraceptive: Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol ↓ ethinyl estradiol
Macrolide Antibiotic:
azithromycin

↑ azithromycin
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Inhaled/nasal steroid: Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Antidepressant: trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.


Table name:
 Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
DRUG EFFECT
Monoamine Oxidase
(MAO) Inhibitors
Hypertension


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 7  Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose  
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazaepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevira LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroca LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): •Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events.
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 18  Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety(Risperidone + 9- Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
*Change relative to reference
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
blood dyscrasias - see cancer collagen vascular disease congestive heart failure
CONTRAINDICATIONS


diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice



hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency




Table name:
Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials























Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†























Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†






















Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.



acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide

































diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine

































lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone

































propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton



































Table name:
edema hereditary coumarin resistance hyperlipemia

hypothyroidism nephrotic syndrome


Table name:
Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†








Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†








Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†











Table name:
Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.

alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone









cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate









6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone









propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage











Table name:
Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list in not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants carbamazepine
Anti-HIV Agents indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide
Benzodiazepines alprazolam, diazepam, midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics (repaglinide)
Opiate Analgesics fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals amphotericin B
Other ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide
Decrease plasma concentration of itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents nevirapine, efavirenz
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
Increase plasma concentration of itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Anti-HIV Agents indinavir, ritonavir


Table name:
Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics pimozide
Antiarrhythmics dofetilide, quinidine
Benzodiazepines oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers Nisoldipine, felodipine
Ergot Alkaloids dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors lovastatin, simvastatin
Opiate Analgesics levacetylmethadol (levomethadyl), methadone


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
  Drug or Drug Class   Effect
  Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
  Drugs that alter thyroid hormone secretion
  Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
  Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
  Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
  Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
  Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
  Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
  Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)


Table name:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 8: Established Drug Interactions with Didanosine
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules.
   ciprofloxacin
   ↓ ciprofloxacin
   concentration
Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin.
   delavirdine
   ↓ delavirdine
   concentration
Administer didanosine 1 hour after delavirdine.
   ganciclovir
   ↓ didanosine
   concentration
If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
   indinavir
   ↓ indinavir
   concentration
Administer didanosine 1 hour after indinavir.
   methadone
   ↓ didanosine
   concentration
Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load.
   nelfinavir
   ↓ No interacion
   1 hour after
   didanosine
Administer nelfinavir 1 hour after didanosine.
   tenofovir
disoproxil 
   fumarate
   ↓ didanosine
   concentration
A dose reduction of didanosine to the following dosage once daily is recommended.a
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Didanosine and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, didanosine should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine­-associated toxicities and clinical response.


Table name:
Table 9: Predicted Drug Interactions with Didanosine
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]
   Drugs that may cause pancreatic toxicity
↑ risk of pancreatitis
   Use only with extreme cautiona
   Neurotoxic drugs
↑ risk of neuropathy
   Use with cautionb
   Antacids containing magnesium or aluminum
↑ side effects associated
with antacid components
   Use caution with Didanosine Pediatric Powder for Oral Solution
   Azole antifungals
↓ ketoconazole or
Itraconazole
concentration
   Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine.
   Quinolone antibiotics (see also ciprofloxacin in Table 8)
↓ quinolone concentration
   Consult package insert of the quinolone.
   Tetracycline antibiotics
↓ antibiotic concentration
   Consult package insert of the tetracycline.


Table name:
CONCOMITANT  DRUG CLINICAL EFFECT(S)        
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment 
Estrogen-containing oral Contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine   

↓ levonorgestrel
Decreased lamotrigine levelsapproximately 50%. 

Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide  ↓ lamotrigine 
 ? CBZ epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine 
 
? valproate 
Increased lamotrigine concentrations slightly more than 2-fold.

Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
CONCOMITANT DRUGCLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agentsAdditive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agentsAdditive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressantsAdditive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressantsAdditive drowsiness and CNS depression
DisulfiramA reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
FluoxetineA 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbituratesDecreased clearance of these agents, presumably via competitive inhibition of metabolism
TheophyllineIncreased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
OpioidsCross-tolerance and mutual potentiation
NaltrexoneOral THC effects were enhanced by opioid receptor blockade.
AlcoholIncrease in the positive subjective mood effects of smoked marijuana


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaledamoxicillin
ampicillin, with or without sulbactamatenolol
azithromycincaffeine, dietary ingestion
cefaclorco-trimoxizole (trimethoprim and sulfamethoxazole)
diltiazemdirithromycin
enfluranefamotidine
felodipinefinasteride
hydrocortisoneisoflurane
isoniazidisradipine
influenza vaccineketoconazole
lomefloxacinmebendazole
medroxyprogesteronemethylprednisolone
metronidazolemetoprolol
nadololnifedipine
nizatidinenorfloxacin
ofloxacinomeprazole
prednisone, prednisoloneranitidine
rifabutinroxithromycin
sorbitol (purgative doses do not inhibit theophylline absorption)sucralfate
terfenadineterbutaline, systemic
tocainidetetracycline


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Drug or Drug Class
Dopamine / Dopamine Agonists Glucocorticoids Octreotide
Effect - Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥1 μg/kg/min); Glucocorticoids (hydrocortisone≥100 mg/day or equivalent); Octreotide ( >100 μg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Drug or Drug Class
Aminoglutethimide
Amiodarone
Iodide
(including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Effect - Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Drug or Drug Class
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Effect - Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Drug or Drug Class
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Sucralfate
Effect - Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may decrease serum TBG concentration
Androgens / Anabolic Steroids Glucocorticoids
Asparaginase Slow Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Drug or Drug Class
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Effect - Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Drug or Drug Class
Carbamazepine Hydantoins Phenobarbital Rifampin
Effect - Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Drug or Drug Class
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥4 mg/day)
Propylthiouracil (PTU)
Effect - Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Drug or Drug Class
Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives
Effect - Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Drug or Drug Class
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Effect - Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Drug or Drug Class
Antidiabetic Agents
- Biguanides
- Meglitinides
- Thiazolidinediones
- Sulfonylureas
- Insulin
Effect - Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Drug or Drug Class
Cardiac Glycosides
Effect - Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Drug or Drug Class
Cytokines - Interferon-α - Interleukin-2
Effect - Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Drug or Drug Class
Growth Hormones - Somatrem - Somatropin
Effect - Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Drug or Drug Class
Ketamine
Effect - Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Drug or Drug Class
Methylxanthine Bronchodilators - (e.g., Theophylline)
Effect - Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Drug or Drug Class
Radiographic Agents
Effect - Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Drug or Drug Class
Sympathomimetics
Effect - Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Drug or Drug Class
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol
(excessive topical use)
Thiazide Diuretics
Effect - These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol,  systemic and inhaledfelodipinefinasteridenizatidinenorfloxacin
amoxicillinhydrocortisoneofloxacin
ampicillin,   with or without sulbactamisofluraneisoniazidomeprazoleprednisone, prednisolone
atenololisradipineranitidine
azithromycininfluenza vaccinerifabutin
caffeine,   dietary ingestionketoconazolelomefloxacinroxithromycinsorbitol
cefaclormebendazole        (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole)medroxyprogesteronemethylprednisolone   inhibit theophylline   absorption)
diltiazemmetronidazolesucralfate
dirithromycinmetoprololterbutaline, systemic
enfluranenadololterfenadine
famotidinenifedipinetetracycline
tocainide
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Agents Prescribing
Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem
Do not exceed 10 mg
simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg
simvastatin daily
Grapefruit juice
Avoid large quantities of
grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Valproic acid Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine gluronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
   Estrogen-containing oral
   contraceptive preparations
   containing 30 mcg
   ethinylestradiol and
   150 mcg levonorgestrel
↓ lamotrigine
 
 
 
 
↓ levonorgestrel
Decreased lamotrigine levels
approximately 50%.
 
 
 
Decrease in levonorgestrel
component by 19%.
   Carbamazepine (CBZ) and
   CBZ epoxide
↓ lamotrigine
 
 
 
? CBZ epoxide
Addition of carbamazepine
decreases lamotrigine
concentration approximately
40%.
 
May increase CBZ epoxide
levels
   Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine
concentration approximately
40%.
   Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine
concentration approximately
40%.
   Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
   Valproate
↑ lamotrigine
 
 
 
? valproate
Increased lamotrigine
concentrations slightly more
than 2-fold.
 
Decreased valproate
concentrations an average of
25% over a 3-week period
then stabilized in healthy
volunteers; no change in
controlled clinical trials in
epilepsy patients.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 5: AED Drug Interactions with Oxcarbazepine
1nc denotes a mean change of less than 10%
2Pediatrics
3Mean increase in adults at high doses of immediate-release oxcarbazepine
AED
Coadministered
(daily dose)
IR-
Oxcarbazepine
(daily dose)
Influence of IR-
Oxcarbazepine on
AED Concentration
Mean Change [90%
Confidence Interval]
Influence of AED on
MHD Concentration
(Mean Change, 90%
Confidence Interval)
Recommendation
Carbamazepine
(400 – 2000 mg)
900 mg nc1 40% decrease
[CI: 17% decrease, 57%
decrease]
Consider initiating
Oxtellar XR™ at
a higher dose.
Monitor and
titrate dose to
desired clinical
effect (see 2.6)
Phenobarbital
(100 – 150 mg)
600 – 1800 mg 14% increase
[CI: 2% increase, 24%
increase]
25% decrease
[CI: 12% decrease, 51%
decrease]
Phenytoin
(250 – 500 mg)
600 – 1800
>1200-2400
nc1,2
up to 40% increase3
[CI: 12% increase, 60%
increase]
30% decrease
[CI: 3% decrease, 48%
decrease]
Valproic Acid
(400 – 2800 mg)
600-1800 nc1 18% decrease
[CI: 13% decrease, 40%
decrease]
Monitor. Dose
adjustment of
Oxtellar XR™
may not be
needed.


Table name:
aDrugs That May Increase Tacrolimus Blood Concentrations
  a) This table is not all inclusive.
  b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients.
  c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.
 Calcium  Antifungal  Macrolide
 Channel Blockers  Agents  Antibiotics
 diltiazem  clotrimazole  clarithromycin
 nicardipine  fluconazole  erythromycin
 nifedipine  itraconazole  troleandomycin
 verapamil  ketoconazoleb
 voriconazole
 Gastrointestinal  Other  
 Prokinetic Agents  Drugs  
 cisapride  bromocriptine  
 metoclopramide  chloramphenicol  
   cimetidine  
   cyclosporine  
   danazol  
   ethinyl estradiol  
   methylprednisolone  
   lansoprazolec  
   omeprazole  
   protease inhibitors  
   nefazodone  
   magnesium-aluminum-hydroxide  


Table name:
aDrugs That May Decrease Tacrolimus Blood Concentrations
  a) This table is not all inclusive.
 Anticonvulsants  Antimicrobials
 carbamazepine  rifabutin
 phenobarbital  caspofungin
 phenytoin  rifampin
 Herbal Preparations  Other Drugs
 St. John’s Wort  sirolimus


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-    containing radiographic    contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide








Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone Iodide (including iodine- containing Radiographic contrast agents)


Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate











Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)






Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , Ieading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)



Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol  (excessive topical use) Thiazide Diuretics










These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
  
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
DRUG DISCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding


Table name:
DRUG DISCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying agents Increases plasma salicylate levels.
Alkcanizing agents Decreased plasma salicylate levels.


Table name:
DRUG DISCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg Q12h)
Recommendations for Voriconazole
Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects, and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400mg Q12h)
(CYP450 Induction)
Significantly Reduced Contraindicated
Low-dose Ritonavir (100mg Q12h)
(CYP450 Induction)
Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)

Careful assessment of voriconazole effectiveness


Table name:
Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400 mg Q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low-dose Ritonavir (100mg Q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions).
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with VFEND

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC
40% decrease
CBZ epoxideb NC
NE
Valproic acid
11% decrease 14% decrease
Phenobarbital NC NE
Primidone
NC NE
Lamotrigine
NC at TPM doses up to 400 mg/day 13% decrease


Table name:
May Require a Decrease in Dose at Cessation of Smoking Possible Mechanism
Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline Deinduction of hepatic enzymes on smoking cessation.
Insulin Increase of subcutaneous insulin absorption with smoking cessation.
Adrenergic antagonists (e.g. prazosin, labetalol) Decrease in circulating catecholamines with smoking cessation.
May Require an Increase in Dose at Cessation of Smoking Possible Mechanism
Adrenergic agonists (e.g. isoproterenol, phenylephrine) Decrease in circulating catecholamines with smoking cessation.


Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
Up to 1 year
Other  drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials:
artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↑ lumefantrine
↔ darunavir
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents:
NS3-4A protease inhibitors:

boceprevir
telaprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15)

Mean (±SD)
Bioavailability 63% (34 to 108%)Range
Clearance (mL/min) 165 (55)
Volume of Distribution (L) 76 (14)
Half-Life (hours) 6.2 (2.1)


Table name:
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men

Mean (± SD)

45 to 60 years old (n=12) ≥70 years old (n=12)
AUC (ng·hr/mL) 389 (98) 463 (186)
Peak Concentration (ng/mL) 46.2 (8.7) 48.4 (14.7)
Time to Peak (hours) 1.8 (0.7) 1.8 (0.6)
Half-Life (hours)First-dose values; all other parameters are last-dose values 6.0 (1.5) 8.2 (2.5)


Table name:
Table 5 Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Boceprevir or Concomitant Drug Recommendations
Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine

↑ antiarrhythmics

Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS.

digoxin ↑ digoxin Digoxin concentrations increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating VICTRELIS. Continue monitoring digoxin concentrations; consult the digoxin prescribing information for information on titrating the digoxin dose.
Anticoagulant: warfarin ↑ or ↓ warfarin Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely.
Antidepressants: trazodone, desipramine ↑ trazodone
↑ desipramine
Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine.
 
escitalopram ↓escitalopram Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS.
Antifungals: ketoconazoleThese combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction., itraconazole, posaconazole, voriconazole ↑ boceprevir

↑ itraconazole
↑ ketoconazole
↑ posaconazole
↑ voriconazole
Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day.
Anti-gout: colchicine ↑ colchicine Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors.

Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS.

Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin ↑ clarithromycin Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function.
Antimycobacterial:
rifabutin
↓ boceprevir
↑ rifabutin
Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended.
Calcium Channel Blockers, dihydropyridine: felodipine, nifedipine, nicardipine ↑ dihydropyridine calcium channel blockers Plasma concentrations of dihydropyridine calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended.
Corticosteroid, systemic: dexamethasone ↓ boceprevir Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary.
prednisone ↑ prednisone Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. No dose adjustment of prednisone is necessary when co-administered with VICTRELIS. Patients receiving prednisone and VICTRELIS should be monitored appropriately.
Corticosteroid, inhaled: budesonide, fluticasone ↑ budesonide
↑ fluticasone
Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations.
Endothelin Receptor Antagonist: bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely.
HIV Integrase Inhibitor:
raltegravir
↔ raltegravir No dose adjustment required for VICTRELIS or raltegravir.
HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination.

etravirine ↓ etravirine Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed.
HIV Protease Inhibitors: atazanavir/ritonavir ↓ atazanavir
↓ ritonavir
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.

darunavir/ritonavir ↓ darunavir
↓ ritonavir
↓ boceprevir
Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended.

lopinavir/ritonavir ↓ lopinavir
↓ ritonavir
↓ boceprevir
Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended.

ritonavir ↓ boceprevir When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.
HMG-CoA Reductase Inhibitors: atorvastatin ↑ atorvastatin Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS.
 
pravastatin ↑ pravastatin Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted.
Immunosuppressants: cyclosporine tacrolimus sirolimus ↑cyclosporine
Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects.
 
↑tacrolimus
Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.
 
↑sirolimus
Blood concentrations of sirolimus are expected to increase significantly when administered with VICTRELIS. Close monitoring of sirolimus blood levels is recommended.
Inhaled beta-agonist: salmeterol ↑ salmeterol Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol.
Narcotic Analgesic/Opioid Dependence: methadone ↓ R-methadone Plasma concentrations of R-methadone decreased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of methadone or VICTRELIS is recommended. Individual patients may require additional titration of their methadone dosage when VICTRELIS is started or stopped to ensure clinical effect of methadone.

buprenorphine/naloxone ↑ buprenorphine/naloxone Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or VICTRELIS is recommended.
Oral hormonal contraceptives: drospirenone/ethinyl estradiol ↑ drospirenone
↓ ethinyl estradiol
Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia [see Contraindications (4)].

norethindrone/ethinyl estradiol ↓ ethinyl estradiol
↔ norethindrone
Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir [see Clinical Pharmacology (12.3)]. Coadministration of VICTRELIS with a combined oral contraceptive containing ethinyl estradiol and at least 1 mg of norethindrone is not likely to alter the effectiveness of this combined oral contraceptive [see Use in Specific Populations (8.1)].

Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of REVATIO® (sildenafil) or ADCIRCA® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS [see Contraindications (4)].

Use of PDE5 inhibitors for erectile dysfunction:
Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses:

Sildenafil: 25 mg every 48 hours

Tadalafil: 10 mg every 72 hours

Vardenafil: 2.5 mg every 24 hours
Proton Pump Inhibitor: omeprazole ↔ omeprazole No dose adjustment of omeprazole or VICTRELIS is recommended.
Sedative/hypnotics: alprazolam; IV midazolam ↑ midazolam
↑ alprazolam
Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCSS (0-12h) (Extent of systemic exposure)
Erythromycin    (500 mg every 8 hrs) +82% +109%
Ketoconazole    (400 mg once daily) +135% +164%


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Interaction Drug Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A4 (tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers) Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)
Digoxin Monitor digoxin plasma concentrations (7.12)
Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections (7.6, 7.13)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
DRUG EFFECT
Monoamine Oxidase
(MAO) Inhibitors
Hypertension


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem
Do not exceed 10 mg simvastatin daily 
Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.

   ganciclovir

   ↑ didanosine concentration

If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-
associated toxicity.

   methadone

   ↓ didanosine concentration

If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients
should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring
for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.

   nelfinavir

   No interaction 1 hour after didanosine

Administer nelfinavir 1 hour after didanosine delayed-release capsules.

   tenofovir disoproxil fumarate

   ↑ didanosine concentration

A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal
(400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]

   Drugs that may cause pancreatic toxicity

↑ risk of pancreatitis

   Use only with extreme caution.a

   Neurotoxic drugs

↑ risk of neuropathy

   Use with caution.b


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓Amprenavir

↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓Amprenavir

↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily.

Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin   ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Potential Drug Interactions:
   
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
   dietary ingestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Drugs That May Potentiate Renal Dysfunction
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole     melphalan   azapropazon colchicine diclofenac naproxen sulindac       cimetidine ranitidine  
Antifungals
amphotericin B ketoconazole   Immunosuppressives
tacrolimus  
Other Drugs
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil   fluconazole itraconazole ketoconazole voriconazole   azithromycin clarithromycin erythromycin quinupristin/ dalfopristin   methylprednisolone   allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives


Table name:
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug ClassEffect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine AgonistsGlucocorticoidsOctreotideUse of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min);Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
AminoglutethimideAmiodarone Iodide (including iodine-containing Radiographiccontrast agents)LithiumMethimazolePropylthiouracil (PTU)SulfonamidesTolbutamideLong-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
AmiodaroneIodide (including iodine-containing Radiographic contrast agents)Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids- Aluminum &Magnesium Hydroxides- SimethiconeBile Acid Sequestrants- Cholestyramine- ColestipolCalcium CarbonateCation Exchange Resins- KayexalateFerrous SulfateOrlistatSucralfateConcurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport – but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
ClofibrateEstrogen-containing oral contraceptives Estrogens (oral)Heroin/Methadone5-FluorouracilMitotaneTamoxifenAndrogens/Anabolic SteroidsAsparaginaseGlucocorticoidsSlow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)HeparinHydantoinsNon-Steroidal Anti-Inflammatory Drugs- Fenamates- PhenylbutazoneSalicylates (> 2 g/day)Administration of these agents with levothyroxine results in an initial transient increase in FT4.Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
CarbamazepineHydantoinsPhenobarbitalRifampinStimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5’-deiodinase activity
AmiodaroneBeta-adrenergic antagonists- (e.g., Propranolol> 160 mg/day)Glucocorticoids- (e.g., Dexamethasone≥ 4 mg/day)Propylthiouracil (PTU)Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)- Coumarin Derivatives- Indandione DerivativesThyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin timeshould be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants- Tricyclics (e.g., Amitriptyline)- Tetracyclics (e.g., Maprotiline)- Selective SerotoninReuptake Inhibitors(SSRIs; e.g., Sertraline)Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline inpatients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents- Biguanides- Meglitinides- Sulfonylureas- Thiazolidediones- InsulinAddition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac GlycosidesSerum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines- Interferon-α- Interleukin-2Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients, and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and –γ have not been reported to cause thyroid dysfunction.
Growth Hormones- Somatrem- SomatropinExcessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
KetamineConcurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators- (e.g., Theophylline)Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic AgentsThyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
SympathomimeticsConcurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral HydrateDiazepamEthionamideLovastatinMetoclopramide6-MercaptopurineNitroprussidePara-aminosalicylate sodiumPerphenazineResorcinol (excessivetopical use)Thiazide DiureticsThese agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓=Decreased (induces lamotrigine glucuronidation).
↑=Increased (inhibits lamotrigine glucuronidation).
?=Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
 
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
 
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,lomefloxacin
   systemic and inhaledmebendazole
amoxicillinmedroxyprogesterone
ampicillin,methylprednisolone
   with or without sulbactammetronidazole
atenololmetoprolol
azithromycinnadolol
Caffeine,nifedipine
   dietary ingestionnizatidine
cefactornorfloxacin
co-trimoxazoleofloxacin
   (trimethoprim andomeprazole
   sulfamethoxazole)prednisone, prednisolone
diltiazemranitidine
dirithromycinrifabutin
enfluraneroxithromycin
famotidinesorbitol
felodipine   (purgative doses do not
finasteride   inhibit theophylline
hydrocortisone   absorption)
isofluranesucralfate
isoniazid terbutaline,systemic
isradipineterfenadine
influenza vaccinetetracycline
ketoconazoletocainide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 1 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
  Desloratadine 3-Hydroxydesloratadine
  Cmax AUC
0–24 hrs
Cmax AUC
0–24 hrs
Erythromycin
(500 mg Q8h)
+24% +14% +43% +40%
Ketoconazole
(200 mg Q12h)
+45% +39% +43% +72%
Azithromycin
(500 mg day 1, 250 mg QD × 4 days)
+15% +5% +15% +4%
Fluoxetine
(20 mg QD)
+15% +0% +17% +13%
Cimetidine
(600 mg Q12h)
+12% +19% -11% -3%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments
ANTIVIRALS
Amprenavir 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax No significant change in kinetics. A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine ND Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine No significant change in kinetics. No significant change in kinetics at steady state.
Fosamprenavir/ritonavir 64% ↑ AUC - Drug plus active metabolite 35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir 204% ↑ in AUC 32%↓ in AUC
Lopinavir/ritonavir 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax No significant change in lopinavir kinetics. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir ND 40% ↓ in AUC
Ritonavir 4 fold increase in AUC, 2.5 fold increase in Cmax ND In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133] 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax No significant change in tipranavir kinetics. Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine No significant change in kinetics. Approximately 32%↓ in Cmax and AUC A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS 82% ↑ in AUC No significant change in steady-state plasma concentrations
Itraconazole ND 70% to 75% ↓ in Cmax and AUC One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole 31%↑ Cmax, 72%↑ AUC 43%↓ Cmax, 49%↓ AUC If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole 195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone ND Approximately 27% to 40% ↓ in AUC Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim No significant change in Cmax and AUC Approximately 15% to 20% ↓ in AUC In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin No PK interaction No PK interaction
Clarithromycin Approximately 77% ↑ in AUC Approximately 50%↓ in AUC Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol ND No significant change in AUC or Cmax
Isoniazid ND Pharmacokinetics not affected
Pyrazinamide ND ND Study data being evaluated.
OTHER
Methadone ND No significant effect No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol ND 35%↓ AUC
20%↓ Cmax
Patients should be advised to use other methods of contraception.
Norethindrone ND 46%↓ AUC Patients should be advised to use other methods of contraception.
Tacrolimus ND ND Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline ND No significant change in AUC or Cmax compared with baseline.


Table name:
Table 5 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
DelavirdineINVIRASE/ritonavir interaction has not been evaluated.
↑ Saquinavir
 
Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor:
EfavirenzSee CLINICAL PHARMACOLOGY: Pharmacokinetics , Table 2 and Table 3 for magnitude of interactions.,
nevirapine
↓ Saquinavir
↔ Efavirenz
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established.
HIV protease inhibitor:
Atazanavir
INVIRASE/ritonavir
↑ Saquinavir
↑ Ritonavir
↔ Atazanavir
Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased.
HIV protease inhibitor:
Indinavir
↑ Saquinavir
 
Effect on indinavir is not well established
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV protease inhibitor:
Lopinavir/ritonavir (coformulated capsule)
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.
HIV protease inhibitor:
Tipranavir/ritonavir
↓ Saquinavir Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV fusion inhibitor:
Enfuvirtide
Saquinavir soft gel capsules/ritonavir
↔ enfuvirtide
No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
Other Agents
Antiarrhythmics:
Lidocaine (systemic)
↑ Antiarrhythmics Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir.
Anticoagulant:
Warfarin
↑ Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin
↓ Saquinavir
 
Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-infective:
Clarithromycin
↑ Saquinavir
↑ Clarithromycin
Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
 
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended:
For patients with renal impairment, the following dosage adjustments should be considered:
  For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungal:
Ketoconazole, itraconazole
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see Table 2 ). Hence, doses of ketoconazole > 200 mg/day are not recommended.
Antimycobacterial:
Rifabutin
↓ Saquinavir
↑ Rifabutin
Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Benzodiazepines:
Alprazolam, clorazepate, diazepam, flurazepam
↑ Benzodiazepines Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine :
Intravenously administered Midazolam
↑ Midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers :
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
↑ Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ Saquinavir Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Digitalis Glycosides:
Digoxin
↑ Digoxin
 
Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see WARNINGS ).
Inhaled/nasal steroid:
Fluticasone
INVIRASE/ritonavir
↑ Fluticasone
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS ).
HMG-CoA reductase inhibitors :
Atorvastatin, rosuvastatin
↑ Atorvastatin
↑ Rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see WARNINGS ).
Immunosuppressants :
Cyclosporine, tacrolimus, rapamycin
↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadone
↓ Methadone Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Oral contraceptives:
Ethinyl estradiol
↓ Ethinyl estradiol Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors):
Sildenafil, vardenafil, tadalafil
↑ Sildenafil
↔ Saquinavir
 
↑ Vardenafil
↑ Tadalafil
Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
 
Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
 
Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Antidepressant:
Trazodone
↑ Trazodone Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered.
Tricyclic antidepressants : Amitriptyline, imipramine ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole ↑ Saquinavir When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.
Herbal Products:
St. John's wort (hypericum perforatum)
↓ Saquinavir Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see WARNINGS ).
Garlic Capsules ↓ Saquinavir Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures .
Fosamprenavir* ↓Amprenavir  
↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite↓Nelfinavir Cmin The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine, Etravirine, Rilpivirine Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:Methadone* ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of  withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:Amiodarone, disopyramide, lidocaine    Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin* ↓ Clarithromycin↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin* ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin* ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Ketoconazole* ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents: Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone* ↓ Ethinyl estradiol  ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)

Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)
Significantly Reduced

Reduced
Contraindicated

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole



Careful assessment of voriconazole effectiveness


Table name:
Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure (Cmax and AUCτ) Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)


Low-dose Ritonavir (100 mg q12h)
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ


Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events
and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 5: Clarithromycin Tissue Concentrations 2 hours after Dose1
1Mean ± (μg/g)
Tissue Clarithromycin Clarithromycin + Omeprazole
Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n = 5)
Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n = 5)
Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n = 4)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high Oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL phenytoina, warfarinb
Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
*nc denotes a mean change of less than 10%PediatricsMean increase in adults at high Oxcarbazepine doses
Carbamazepine 400-2000 900 nc * 40% decrease
[CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
less then 1200-2400
nc * ,
up to 40% increase
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc * 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic
agents
Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other
anticholinergic agents
Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other
tricyclic antidepressants
Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium,
opioids, buspirone, antihistamines, muscle relaxants,
other CNS depressants
Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o
man who smoked marijuana; confirmed by dechallenge and
rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20
mg/day fluoxetine X 4 wks became hypomanic after
smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via
competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of
marijuana; effect similar to that following smoking tobacco
Opioids Cross-tolerance and mutual potentiation
Naltrexone Oral THC effects were enhanced by opioid receptor
blockade.
Alcohol Increase in the positive subjective mood effects of smoked
marijuana


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*) Risperidone DoseRecommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6)Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 - Re-evaluate dosing. Donot exceed 8 mg/day
Enzyme (CYP3A/PgP inducers)Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards.Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum and Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2       Effects of Paroxetine on Other Drugs
Concomitant
Drug Name


Effect of Paroxetine on
Other Drugs
Clinical Recommendations
Thioridazine



Increased plasma concentrations of thioridazine

Potential QTc prolongation
Concomitant use of thioridazine and BRISDELLE is
contraindicated.
Pimozide



Increased plasma concentrations
of pimozide. Potential QTc
prolongation
Concomitant use of pimozide and BRISDELLE is
contraindicated.
Tamoxifen


Reduced plasma concentrations
of active tamoxifen metabolite
Consider avoiding concomitant use of tamoxifen
and BRISDELLE.

Tricyclic
Antidepressant
(TCA)
(e.g., Desipramine)

Increased plasma concentrations
and elimination half-life
Plasma TCA concentrations may need to be
monitored and the dose of TCA may need to be
reduced if a TCA is co-administered with
BRISDELLE. Monitor tolerability.
Risperidone



Increased plasma concentrations
of risperidone
A lower dosage of risperidone may be necessary
(see the Full Prescribing Information for
risperidone). Monitor tolerability.
Atomoxetine



Increased exposure of
atomoxetine
A lower dosage of atomoxetine may be necessary
(see Full Prescribing Information for atomoxetine).
Monitor tolerability.
Drugs Highly Bound
to Plasma Protein
(e.g., Warfarin)

Increased free plasma
concentrations
The dosage of warfarin may need to be reduced.
Monitor tolerability and the International
Normalized Ratio.
Digoxin


Decreased plasma concentrations
of digoxin
Dosage of digoxin may need to be increased.
Monitor digoxin concentrations and clinical effect.
Theophylline



Increased plasma concentrations
of theophylline
Dosage of theophylline may need to be decreased.
Monitor theophylline concentrations and
tolerability.


Table name:
Table 3       Effects of Other Drugs on Paroxetine
Concomitant
Drug Name


Effect of Concomitant Drug
on Paroxetine


Clinical Recommendations

Phenobarbital

Decreased paroxetine exposure
 


Phenytoin

Decreased paroxetine exposure

 


Fosamprenavir/
Ritonavir


Decreased plasma concentration
of paroxetine
No dose adjustment for BRISDELLE.

Monitor clinical effect of BRISDELLE.
Cimetidine Increased plasma concentration
of paroxetine

 


Table name:
Antibiotics Antineoplastic   Antifungals           Anti-
Inflammatory
Drugs
Gastrointestinal 
Agents
Immunosuppressives     Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin Bketoconazole azapropazoncolchicine diclofenacnaproxen sulindac cimetidine ranitidine tacrolimus fibric acid
derivatives (e.g., bezafibrate, 
fenofibrate) methotrexate


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs                   
diltiazem fluconazole azithromycin methylprednisolone     allopurinol                           
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
quinupristin/ colchicine
voriconazole dalfopristin danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/DietarySupplements
nafcillin carbamazepine bosentan  St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax  
Enzyme (CYP2D6) Inhibitors          
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day 4 mg/day 1.6 -
  40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
DelavirdineINVIRASE/ritonavir interaction has not been evaluated.
↑ Saquinavir

Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor:
EfavirenzSee Drug Interactions (7) , Table 5 and Table 6 for magnitude of interactions.,
nevirapine
↓ Saquinavir
↔ Efavirenz


Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor:
Atazanavir
INVIRASE/ritonavir
↑ Saquinavir
↑ Ritonavir
↔ Atazanavir
Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir [see Warnings and Precautions (5.2)].
HIV-1 protease inhibitor:
Indinavir
↑ Saquinavir

Effect on indinavir is not well established
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor:
Lopinavir/ritonavir (coformulated tablet)
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.

Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor:
Tipranavir/ritonavir
↓ Saquinavir
Combining saquinavir with tipranavir/ritonavir is not recommended.

HIV-1 fusion inhibitor:
Enfuvirtide
Saquinavir soft gel capsules/ritonavir
↔ enfuvirtide
No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
HIV-1 CCR5 antagonist:
Maraviroc
↑ Maraviroc Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Ibutilide
Sotalol
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Anticoagulant:
Warfarin
↑ Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin
↓ Saquinavir

Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-gout:
Colchicine
↑ Colchicine Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Anti-infective:
Clarithromycin
↑ Saquinavir
↑ Clarithromycin
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Erythromycin
Halofantrine
Pentamidine
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Antifungal:
Ketoconazole,
itraconazole
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial:
Rifabutin
↔ Saquinavir
↑ Rifabutin
↔ Ritonavir

No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin.

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination.

Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepines :
Alprazolam, clorazepate, diazepam, flurazepam
↑ Benzodiazepines Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine :
Intravenously administered Midazolam
↑ Midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers :
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
↑ Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ Saquinavir
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.
Digitalis Glycosides: Digoxin ↑ Digoxin

Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists:
Bosentan
↑ Bosentan Coadministration of bosentan in patients on INVIRASE/ritonavir:

In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir.

After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist:
Salmeterol
↑ Salmeterol Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid:
Fluticasone
INVIRASE/ritonavir
↑ Fluticasone
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
HMG-CoA reductase inhibitors :
Atorvastatin
↑ Atorvastatin
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.
Immunosuppressants :
Cyclosporine, tacrolimus, rapamycin
↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadone
↓ Methadone Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.

Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Neuroleptics:
Clozapine
Haloperidol
Mesoridazine
Phenothiazines
Thioridazine
Ziprasidone
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives:
Ethinyl estradiol
↓ Ethinyl estradiol Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors):
Sildenafil, vardenafil, tadalafil
↑ Sildenafil
↔ Saquinavir

↑ Vardenafil
↑ Tadalafil

Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca®) with INVIRASE/ritonavir:

Coadministration of Adcirca in patients on INVIRASE/ritonavir:

In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on Adcirca:

Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, imipramine
↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole ↑ Saquinavir When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products:
St. John's wort (hypericum perforatum)
↓ Saquinavir Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Garlic Capsules ↓ Saquinavir Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED
Coadministered
AED
Concentration
Felbamate
Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)
*CBZ epoxide

Phenobarbital


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, lomefloxacin
  systemic and inhaled mebendazole
amoxicillin medroxyprogesterone
ampicillin, methylprednisolone
  with or without sulbactam metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine, nifedipine
  dietary ingestion nizatidine
cefactor norfloxacin
co-trimoxazole ofloxacin
  (trimethoprim and omeprazole
  sulfamethoxazole) prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol
felodipine   (purgative doses do not
finasteride   inhibit theophylline
hydrocortisone   absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine
Dose
(mg/day)
Influence of
Oxcarbazepine on
AED
Concentration
(Mean Change,
90% Confidence
Interval)
Influence of
AED on MHD
Concentration
(Mean Change,
90% Confidence
Interval)
Carbamazepine 400-2000 900 nc* 40% decrease
    [CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase 25% decrease
      [CI: 2% increase,
24% increase]
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800 nc , 30% decrease
    >1200-2400 up to 40% increase [CI: 3% decrease,
48% decrease]
      [CI: 12% increase,
60% increase]
 
Valproic acid 400-2800 600-1800 nc 18% decrease
        [CI: 13% decrease,
40% decrease]



Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin (2.3, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations for LIPTRUZET
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil Avoid LIPTRUZET
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary.
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 10/20 mg LIPTRUZET daily.
HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir) Do not exceed 10/40 mg LIPTRUZET daily.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20–40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33–100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol, systemic and inhaled  medroxyprogesterone
 amoxicillin  methylprednisolone
 ampicillin, with or without sulbactam  metronidazole
 atenolol  metoprolol
 azithromycin  nadolol
 caffeine, dietary ingestion  nifedipine
 cefaclor  nizatidine
 co-trimoxazole  norfloxacin
   (trimethoprim and sulfamethoxazole)  ofloxacin
 diltiazem  omeprazole
 dirithromycin  prednisone, prednisolone
 enflurane  ranitidine
 famotidine  rifabutin
 felodipine  roxithromycin
 finasteride  sorbitol
 hydrocortisone    (purgative doses do not inhibit
 isoflurane      theophylline absorption)
 isoniazid  sucralfate
 isradipine  terbutaline, systemic
 influenza vaccine  terfenadine
 ketoconazole  tetracycline
 lomefloxacin  tocainide
 mebendazole  


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Table 4: Clarithromycin Tissue Concentrations 2 hours after DoseMean ± (ug/g)
Tissue Clarithromycin Clarithromycin + Omeprazole
Antrum 10.48 ± 2.01 (n=5) 19.96 ± 4.71 (n=5)
Fundus 20.81 ± 7.64 (n=5) 24.25 ± 6.37 (n=5)
Mucus 4.15 ± 7.74 (n=4) 39.29 ± 32.79 (n=4)


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone +
9-Hydroxy-
Risperidone Ratio*)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/
PgP inducers)
Inducers
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient𕢙s usual dose
Enzyme (CYP3A)
Inhibitors
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0–24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine
or Concomitant Drug
Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and
Norethindrone
↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir

↑ Nevirapine
Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is coadministered with
700 mg/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓ Lopinavir A dose increase of lopinavir/ritonavir tablets to 500 mg/125 mg twice daily is recommended when used in combination with nevirapine.
A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily.

Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class Examples of Drugs
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-half when used concomitantly (2.6, 7.1), except when used as adjunctive treatment with antidepressants (2.6) CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug concentrations; double ABILIFY dose when used concomitantly (2.6, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine.
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir.
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir.
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine
vinblastine
↑ anticancer agents Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents.

Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
Anticoagulant:
warfarin
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
dexamethasone
↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Narcotic Analgesic:
methadone*
↓ methadone Dosage of methadone may need to be increased when co-administered with KALETRA.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓ lamotrigine    
↓ levonorgestrel
Decreased lamotrigine levels approximately 50%.   Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine   

? CBZ epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine   

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.  
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast,
moricizine,
omeprazole, phenobarbital, phenytoin,
cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir,
aprepitant,
bosentan,
carbamazepine, efavirenz,
etravirine,
modafinil, nafcillin,
phenytoin,
pioglitazone, prednisone,
rifampin,
rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin,
heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole,
prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen,
ibuprofen, indomethacin, ketoprofen,
ketorolac, mefenamic acid, naproxen,
oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.


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Table 5: Established Drug Interactions Based on Studies with Didanosine or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine
↑Indicates increase.
↓Indicates decrease.
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate ↑didanosine concentration A dose reduction of didanosine to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


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Table 6: Predicted Drug Interactions with Didanosine
↑ Indicates increase.
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs ↑risk of neuropathy Use with caution.[See Warnings and Precautions (5.5).]


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*Range
Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15)

 
Mean (± SD)
   Bioavailability
   63% (34-108%)*   
   Clearance (mL/min)
165 (55)
   Volume of Distribution (L)   
76 (14)
   Half-Life (hours)
6.2 (2.1)


Table name:
*First-dose values; all other parameters are last-dose values
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men

 
Mean (± SD)
  45 to 60 years old  (n=12)

  ≥70 years old   (n=12)

   AUC (ng•hr/mL)
389 (98)
463 (186)
   Peak Concentration (ng/mL)   
46.2 (8.7)
48.4 (14.7)
   Time to Peak (hours)
1.8 (0.7)
1.8 (0.6)
   Half-Life (hours)*
6 (1.5)
8.2 (2.5)


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference


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Table 7 Summary of AED Interactions with Oxcarbazepine
1 nc denotes a mean change of less than 10% 2 Pediatrics 3 Mean increase in adults at high oxcarbazepine doses
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 > 1200 to 2400 nc 1,2 up to 40% increase3 [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease [CI: 13% decrease, 40% decrease]


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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0-24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


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Table 6: Selected Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


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Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, erythromycin, clarithromycin, 
   telithromycin, HIV protease inhibitors, nefazodone
   Avoid simvastatin
   Gemfibrozil, cyclosporine, danazol
   Do not exceed 10 mg simvastatin daily
   Amiodarone, verapamil
   Do not exceed 20 mg simvastatin daily
   Diltiazem    Do not exceed 40 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


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DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


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DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


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DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


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Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


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Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


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Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.1).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
     
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
     
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
 
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
     
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants Increased bleeding


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
Up to 1 year
Other drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed
* Change relative to reference


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem
Do not exceed 10 mg simvastatin daily 
Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Antibiotics ciprofloxacin, gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole
Antineoplastics melphalan
Antifungals amphotericin B, ketoconazole
Anti-Inflammatory Drugs azapropazon, colchicine, diclofenac, naproxen, sulindac
Gastrointestinal Agents cimetidine, ranitidine
Immunosuppressives tacrolimus
Other Drugs fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Antibiotics azithromycin, clarithromycin, erythromycin, quinupristin/dalfopristin
Antifungals fluconazole, itraconazole, ketoconazole, voriconazole
Calcium Channel Blockers diltiazem, nicardipine, verapamil
Glucocorticoids methylprednisolone
Other Drugs allopurinol, amiodarone, bromocriptine, colchicine, danazol, metoclopromide, imatinib, nefazodone, oral contraceptives


Table name:
Antibiotics nafcillin, rifampin
Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Other Drugs/Dietary Supplements bosentan, octreotide, orlistat, sulfinpyrazone, terbinafine, ticlopidine, St. John’s Wort


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3    metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4   5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2 Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
  ↑ rivaroxaban Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.

Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g.
budesonide,
dexamethasone,
prednisone
↓ lopinavir
↑ glucocorticoids
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor:
boceprevir
↓ lopinavir
↓ boceprevir
↓ ritonavir
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor:
telaprevir
↓ telaprevir
↔ lopinavir
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.:
fluticasone,
budesonide
↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 1. Selected Drugs that are Predicted to Alter the Plasma Concentration of Itraconazole or have their Plasma Concentration Altered by ItraconazoleThis list is not all-inclusive.
Drug Plasma Concentration Increased by Itraconazole
Antiarrhythmics digoxin, dofetilideContraindicated with itraconazole based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.), quinidine, disopyramide
Anticonvulsants carbamazepine
Antimycobacterials rifabutin
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide 
Benzodiazepines alprazolam, diazepam, midazolam, For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers dihydropyridines, (including felodipine and nisoldipine), verapamil
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics
Protease Inhibitors indinavir, ritonavir, saquinavir
Other methadone, levacetylmethadol (levomethadyl), ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl
 
Decrease Plasma Concentration of Itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors nevirapine
 
Increase Plasma Concentration of Itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Protease Inhibitors indinavir, ritonavir


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration
of Lamotrigine or
Concomitant Drug
Clinical Comment 
Estrogen-containing oral 
contraceptive preparations
containing 30 mcg 
ethinylestradiol and 150 mcg
levonorgestrel 
↓ lamotrigine 


↓ levonorgestrel 
Decreased lamotrigine levels 
approximately 50%. 

Decrease in levonorgestrel 
component by 19%. 
Carbamazepine and
carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine
  epoxide 
Addition of carbamazepine 
decreases lamotrigine 
concentration approximately 40%. 
May increase carbamazepine
epoxide levels. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Rifampin 
↓ lamotrigine
Decreased lamotrigine 
AUC approximately 40%. 
Valproate 
↑ lamotrigine 


? valproate 
Increased lamotrigine 
concentrations slightly more than 
2-fold. 
Decreased valproate concentrations 
an average of 25% over a 3-week 
period then stabilized in healthy 
volunteers; no change in controlled 
clinical trials in epilepsy patients. 


Table name:
Oral hypoglycemics Coumarin-type anticoagulants    Phenytoin 
Cyclosporine Rifampin Theophylline
Terfenadine Cisapride Astemizole
Rifabutin Voriconazole Tacrolimus
Short-acting benzodiazepines Triazolam Oral contraceptives
Pimozide Hydrochlorothiazide Alfentanil
Amitriptyline, nortriptyline Amphotericin B Azithromycin
Carbamazepine Calcium channel blockers Celecoxib
Cyclophosphamide Fentanyl Halofantrine
HMG-CoA reductase inhibitors Losartan Methadone
Non-steroidal anti-inflammatory drugs     Prednisone Saquinavir
Sirolimus Vinca alkaloids Vitamin A
Zidovudine    


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 8: Established Drug Interactions with VIDEX
Drug Effect Clinical Comment
↑  Indicates increase.
↓  Indicates decrease.
a  The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine.
ganciclovir ↑ didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with VIDEX with caution. Monitor for didanosine-associated toxicity.
indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir.
methadone ↓ didanosine concentration Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX.
tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX to the following dosage once daily is recommended.a
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) VIDEX and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 9: Predicted Drug Interactions with VIDEX
Drug or Drug Class Effect Clinical Comment
↑  Indicates increase.
↓  Indicates decrease.
a  Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [see Warnings and Precautions (5.1) ].
b  [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme cautiona
Neurotoxic drugs ↑ risk of neuropathy Use with cautionb
Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Pediatric Powder for Oral Solution
Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also ciprofloxacin in Table 8) ↓ quinolone concentration Consult package insert of the quinolone.
Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on ConcentrationIncrease = ↑; Decrease = ↓; No Effect = ↔ Clinical Comment
Antacids:

  antacids
  (e.g., aluminium, magnesium hydroxide, or calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)

↓ rilpivirine (concomitant intake)
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents:

  fluconazole
  itraconazole
  ketoconazole
  posaconazole
  voriconazole
↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
↓ ketoconazole ,
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H2-Receptor Antagonists:

  cimetidine
  famotidine
  nizatidine
  ranitidine
↔ rilpivirine ,
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)

↓ rilpivirine ,
(famotidine taken 2 hours before rilpivirine)
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics:

  clarithromycin
  erythromycin
  telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:

  methadone
↓ R(–) methadone
↓ S(+) methadone
↔ rilpivirine
↔ methadone (when used with tenofovir)
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
NA – Not available/reported
Digoxin concentrations increased > 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
quinine, rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studies but reported no significant changes on digoxin exposure.
No additional actions are required.     


Table name:
Drugs that Affect Renal Function Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 7  Summary of AED Interactions with Trileptal
AED
Coadministered
Dose of AED
(mg/day)
Trileptal Dose
(mg/day)
Influence of
Trileptal on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 7. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg Q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
 
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)
Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
 
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
 
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Concomitant Drug
Effect on  Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel

↓ lamotrigine
 
 
 ↓ levonorgestrel

Decreased lamotrigine levels approximately 50%.
 
Decrease in levonorgestrel component by 19%.

Carbamazepine (CBZ)
and CBZ epoxide
↓ lamotrigine

  
 
 ? CBZ epoxide

Addition of carbamazepine decreases lamotrigine concentration approximately 40% 
 
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate

↑ lamotrigine
 
 
 ? valproate

Increased lamotrigine concentrations slightly more than 2-fold.
 
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 8 Established and Other Potentially Significant Drug Interactions With Ganciclovir
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
Zidovudine ↓ Ganciclovir
↑ Zidovudine
Zidovudine and Valcyte each have the potential to cause neutropenia and anemia
Probenecid ↑ Ganciclovir Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine ↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
 Interacting Agents  Prescribing Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol  Contraindicated with simvastatin 
 Verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine   Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Digoxin concentrations increased > 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril 58% 39%
Nitrendipine 57% 15%
Propafenone 35-85% NA
Quinidine 100% NA
Ranolazine 87% 88%
Ritonavir NA 86%
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem 20% NA
Nifedipine 45% NA
Rabeprazole 29% 19%
Telmisartan 20% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in complete heart block.


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug Dosing Schedule Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone) (RatioChange relative to reference) Risperidone Dose Recommendation

Co-administered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
 Drug or Drug Class  Effect
 Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
 Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
 Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
 Drugs that alter thyroid hormone secretion
 Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
 Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
 Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
 Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
 Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
 Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
 Drugs that may decrease T 4 absorption, which may result in hypothyroidism
 Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
 Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
 Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
 Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
 Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
 Drugs that may cause protein-binding site displacement
 Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
 Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
 Carbamazepine
Hydantoins
Phenobarbital
Rifampin
 Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
 Drugs that may decrease T 4 5’-deiodinase activity
 Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
 Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
 Miscellaneous
 Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
 Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
 Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
 Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
 Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
 Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
 Cardiac Glycosides  Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
 Cytokines
- Interferon-α
- Interleukin-2
 Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
 Growth Hormones
- Somatrem
- Somatropin
 Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
 Ketamine  Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
 Methylxanthine Bronchodilators
- (e.g., Theophylline)
 Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
 Radiographic Agents  Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
 Sympathomimetics  Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
 Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
 These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Valproic acid Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine gluronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
   Estrogen-containing oral
   contraceptive preparations
   containing 30 mcg
   ethinylestradiol and
   150 mcg levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine levels
approximately 50%.
Decrease in levonorgestrel
component by 19%.
   Carbamazepine (CBZ) and
   CBZ epoxide
↓ lamotrigine
? CBZ epoxide
Addition of carbamazepine
decreases lamotrigine
concentration approximately
40%.
May increase CBZ epoxide
levels.
   Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine
concentration approximately
40%.
   Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine
concentration approximately
40%.
   Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
   Valproate
↑ lamotrigine
? valproate
Increased lamotrigine
concentrations slightly more
than 2-fold.
Decreased valproate
concentrations an average of
25% over a 3-week period
then stabilized in healthy
volunteers; no change in
controlled clinical trials in
epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, lomefloxacin
systemic and inhaled mebendazole
amoxicillin medroxyprogesterone
ampicillin, methylprednisolone
with or without sulbactam metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine, nifedipine
dietary ingestion nizatidine
cefaclor norfloxacin
co-trimoxazole ofloxacin
(trimethoprim and omeprazole
sulfamethoxazole) prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol
felodipine (purgative doses do not
finasteride inhibit theophylline
hydrocortisone absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily, 7 days 800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 5: Results of Drug Interaction Studies with Stavudine: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values
Drug Stavudine
  Dosage
na    AUC of
Stavudine
 (95% CI)
Cmax of
 Stavudine
(95% CI)
↑ indicates increase
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
q12h for 4 days
40 mg q12h
for 4 days
10   

↑17%
Lamivudine, 150 mg
single dose
40 mg single dose
18   

(92.7-100.6%)
↑12%
(100.3-126.1%)
Nelfinavir, 750 mg
q8h for 56 days
30 to 40 mg q12h
for 56 days
8   




Table name:
Table 6: Results of Drug Interaction Studies with Stavudine: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values
Drug  StavudineDosage  na    AUC of
 Coadministered 
 Drug
(95% CI)
Cmax of
 Coadministered 
 Drug
(95% CI)
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
 q12h for 4 days
40 mg q12h
for 4 days
10   


Lamivudine, 150 mg 
 single dose
40 mg single
dose
18     

(90.5-107.6%)

(87.1-110.6%)
Nelfinavir, 750 mg
 q8h for 56 days
30 to 40 mg q12h
for 56 days
8   




Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUC
τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz**
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg QD)
**** Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUC
τ)
Recommendations for Drug DosageAdjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz**
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministeredwith efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Ritonavir Cmax or AUCτ
Low-dose Ritonavir (100 mg q12h)** Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac(CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*(CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors In Vivo Studies Showed No Significant No dosage adjustment for indinavirwhen coadministered with voriconazole tablets
(CYP3A4 Inhibition) Effects on Indinavir Exposure
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety ( Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 7  Summary of AED Interactions with Trileptal
AED
Coadministered
Dose of AED
(mg/day)
Trileptal Dose
(mg/day)
Influence of
Trileptal on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Interacting Drug Interaction
Multivalent cation - containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors          (e.g., itraconazole,    ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin,    HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class:
Drug Name
Effect on
Concentration
Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine ↑ nelfinavir (Cmin)
↓ delavirdine
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine ↓ nelfinavir (Cmin) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir ↑ nelfinavir
↑ indinavir
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir ↑ nelfinavir
↔ ritonavir
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir ↑ nelfinavir
↑ saquinavir
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital
Phenytoin

↓ nelfinavir

↓ phenytoin
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine ↑ colchicines Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity.

Treatment of gout flares –
co- administration of colchicine in patients on VIRACEPT:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout-flares –
coadministration of colchicine in patients on VIRACEPT:


If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan:
Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin
Rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine
Tacrolimus
Sirolimus
↑ immuno-suppressants
↑ nelfinavir
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol ↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin ↑ azithromycin Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone ↓ methadone Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol
Norethindrone
↓ ethinyl estradiol
↓ norethindrone
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil
Vardenafil
Tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

• Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ].

• The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT:

Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:

Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole ↓ nelfinavir Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and torsade de pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%

↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%

? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold

? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin   colchicine ranitidine
tobramycin Antifungals diclofenac  
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
      (e.g.,bezafibrate, fenofibrate)
methotrexate


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin   amiodarone
verapamil ketoconazole erythromycin   bromocriptine
  voriconazole quinupristin/   colchicine
    dalfopristin   danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:
 
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin  Contraindicated with lovastatin
 Gemfibrozil, cyclosporine  Avoid with lovastatin
 Danazol, diltiazem, dronedarone, verapamil  Do not exceed 20 mg lovastatin daily
 Amiodarone  Do not exceed 40 mg lovastatin daily
 Grapefruit juice  Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz**
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg QD)
**** Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug DosageAdjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz**
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministeredwith efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Ritonavir Cmax or AUCτ
Low-dose Ritonavir (100 mg q12h)** Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors In Vivo Studies Showed No Significant No dosage adjustment for indinavir when coadministered with voriconazole tablets
(CYP3A4 Inhibition) Effects on Indinavir Exposure
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort
(Hypericum perforatum)
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration of Delavirdine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitor
Didanosinea ↓Delavirdine ↓Didanosine Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors
NNRTI ↔Delavirdine ↑NNRTI Combining NNRTIs has not been shown to be beneficial. RESCRIPTOR should not be coadministered with another NNRTI.
HIV-Antiviral Agents: Protease Inhibitors
Indinavira ↑Indinavir A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir ↑Lopinavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavira ↑Nelfinavir ↓Delavirdine Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established (see CLINICAL PHARMACOLOGY: Tables 1 and 2).
Ritonavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavira ↑Saquinavir A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
HIV-Antiviral Agents: CCR5 Inhibitor
Maraviroc ↑Maraviroc Concomitant use of RESCRIPTOR and maraviroc has not been studied. However, RESCRIPTOR is a potent CYP3A4 inhibitor and the maraviroc dose should be reduced during coadministration. Refer to the full prescribing information for maraviroc (SELZENTRY) for dosing recommendations.
Other Agents
Acid blockers: Antacidsa ↓Delavirdine Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines ↑Amphetamines Use with caution.
Antidepressant: Trazodone ↑Trazodone Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiarrhythmics: Bepridil ↑Antiarrhythmics Use with caution. Increased bepridil exposure may be associated with life‑threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin ↑Warfarin It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycina ↑Clarithromycin When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil ↑Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Delavirdine Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil ↑Sildenafil Sildenafil should not exceed a maximum single dose of 25 mg in a 48‑hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin ↑Atorvastatin ↑Cerivastatin ↑Fluvastatin Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone ↑Fluticasone Concomitant use of fluticasone and RESCRIPTOR may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Narcotic analgesic: Methadone ↑Methadone Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol ↑Ethinyl estradiol Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreated when the tablet or oral solution formulation is taken with 2 hours of these products.  Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Anti-diabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction [See Clinical Pharmacology (12.3) (Tables 6 and 7) for Magnitude of Interaction.]
Concomitant Drug Class:
Drug Name
Effect on concentration of INCIVEK or Concomitant Drug Clinical Comment
The direction of the arrow (↑ = increase,= decrease,= no change) indicates the direction of the change in PK.
ANTIARRHYTHMICS
lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine
↑ antiarrhythmics Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir.
digoxinThese interactions have been studied. See Clinical Pharmacology (12.3), Tables 6 and 7. ↑ digoxin
Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
ANTIBACTERIALS
clarithromycin
erythromycin
telithromycin
↑ telaprevir
↑ antibacterials
Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.
ANTICOAGULANT
warfarin ↑ or ↓ warfarin Concentrations of warfarin may be altered when co-administered with telaprevir. The international normalized ratio (INR) should be monitored when warfarin is co-administered with telaprevir.
ANTICONVULSANTS
carbamazepine
phenobarbital
phenytoin
↓ telaprevir
↑ carbamazepine
↑ or ↓ phenytoin
↑ or ↓ phenobarbital
Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin.
Telaprevir may be less effective in patients taking these agents concomitantly.
Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.
ANTIDEPRESSANTS
escitalopram ↔ telaprevir
↓ escitalopram
Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir.
trazodone ↑ trazodone Concomitant use of trazodone and telaprevir may increase plasma concentrations of trazodone which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone is used with telaprevir, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIFUNGALS
ketoconazole
itraconazole
posaconazole
voriconazole
↑ ketoconazole
↑ telaprevir

↑ itraconazole
↑ posaconazole
↑ or ↓ voriconazole
Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir.
Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended.
Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole.
QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole.
Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.
ANTI GOUT
colchicine ↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with telaprevir, due to the risk of colchicine toxicity. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function.
Treatment of gout flares: co-administration of colchicine in patients on telaprevir:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.
If used for prophylaxis of gout flares: co-administration of colchicine in patients on telaprevir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): co-administration of colchicine in patients on telaprevir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
rifabutin ↓ telaprevir
↑ rifabutin
Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.
BENZODIAZEPINES
alprazolam ↑ alprazolam Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted.
parenterally
administered
midazolam
↑ midazolam Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Co-administration of oral midazolam with telaprevir is contraindicated.
zolpidem (non-benzodiazepine sedative) ↓ zolpidem Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.
CALCIUM CHANNEL BLOCKERS
amlodipine ↑ amlodipine Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended.
diltiazem
felodipine
nicardipine
nifedipine
nisoldipine
verapamil
↑calcium channel blockers Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered.
Caution is warranted and clinical monitoring of patients is recommended.
CORTICOSTEROIDS
Systemic
prednisone
methylprednisolone
↑ prednisone
↑ methylprednisolone
Systemic corticosteroids such as prednisone and methylprednisolone are CYP3A substrates. Since telaprevir is a strong CYP3A inhibitor, plasma concentrations of these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended [see Warnings and Precautions (5.1) ].
Systemic
dexamethasone
↓ telaprevir
Systemic dexamethasone induces CYP3A and can thereby decrease telaprevir plasma concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered.
Inhaled/Nasal
fluticasone
budesonide
↑fluticasone
↑ budesonide
Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
ENDOTHELIN RECEPTOR ANTAGONIST
bosentan ↑ bosentan Concentrations of bosentan may be increased when co-administered with telaprevir. Caution is warranted and clinical monitoring is recommended.
HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)
atazanavir/ritonavir ↓ telaprevir
↑ atazanavir
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
darunavir/ritonavir ↓ telaprevir
↓ darunavir
Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.

fosamprenavir/ritonavir ↓ telaprevir
↓ fosamprenavir
Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.
lopinavir/ritonavir ↓ telaprevir
↔ lopinavir
Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.
HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
efavirenz ↓ telaprevir
↓ efavirenz
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
tenofovir disoproxil fumarate ↔ telaprevir
↑ tenofovir
Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.
HMG-CoA REDUCTASE INHIBITORS
atorvastatin
fluvastatin
pitavastatin
pravastatin
rosuvastatin
↑ statin Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevir. Avoid concomitant administration of telaprevir and atorvastatin. For fluvastatin, pitavastatin, pravastatin, and rosuvastatin, caution is warranted and clinical monitoring is recommended. Refer to Contraindications (4) for HMG-CoA reductase inhibitors (lovastatin, simvastatin) that are contraindicated with INCIVEK.
HORMONAL CONTRACEPTIVES/ESTROGEN
ethinyl estradiol
norethindrone
↓ ethinyl estradiol
↔ norethindrone
Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir.
Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Refer also to Contraindications (4) , Warnings and Precautions (5.3) , Use in Specific Populations (8.1) , and Patient Counseling Information (17.2) .
IMMUNOSUPPRESSANTS
cyclosporine
sirolimus
tacrolimus
↑ cyclosporine
↑ sirolimus
↑ tacrolimus
Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.
INHALED BETA AGONIST
salmeterol ↑ salmeterol Concentrations of salmeterol may be increased when co-administered with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INSULIN SECRETAGOGUES
repaglinide ↑ repaglinide Caution is warranted and clinical monitoring is recommended.
NARCOTIC ANALGESIC
methadone ↓ R-methadone
Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of telaprevir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
PDE5 INHIBITORS
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE5 inhibitor-associated adverse events.
QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended.
Co-administration of sildenafil or tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated [see Contraindications (4) ].


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
 Interacting Agents  Prescribing Recommendations
 Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
 Amiodarone, verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose 18-30 years 31-65 years
No fentanyl 6.4 ± 0.0 6.3 ± 0.4
3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%)
6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%)
No midazolam 6.9 ± 0.1 5.9 ± 0.6
25 µg/kg midazolam - 4.9 ± 0.9 (16%)
50 µg/kg midazolam - 4.9 ± 0.5 (17%)


Table name:
Table 4
Dosage of Muscle Relaxant Causing 95% Depression
in Neuromuscular Blockade
Desflurane Concentration Mean ED95 (µg/kg)
Pancuronium Atracurium Succinylcholine Vecuronium
0.65 MAC 60%
N2O/O2
26 123 - -
1.25 MAC 60%
N2O/O2
18 91 - -
1.25 MAC O2 22 120 362 19


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


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Table 9: Established Drug Interactions with Didanosine
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules.
   ciprofloxacin
   ↓ ciprofloxacin
   concentration
Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin.
   delavirdine
   ↓ delavirdine
   concentration
Administer didanosine 1 hour after delavirdine.
   ganciclovir
   ↓ didanosine
   concentration
If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
   indinavir
   ↓ indinavir
   concentration
Administer didanosine 1 hour after indinavir.
   methadone
   ↓ didanosine
   concentration
Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load.
   nelfinavir
   ↓ No interacion
   1 hour after
   didanosine
Administer nelfinavir 1 hour after didanosine.
   tenofovir
disoproxil 
   fumarate
   ↓ didanosine
   concentration
A dose reduction of didanosine to the following dosage once daily is recommended.a
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Didanosine and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, didanosine should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine­-associated toxicities and clinical response.


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Table 10: Predicted Drug Interactions with Didanosine
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]
   Drugs that may cause pancreatic toxicity
↑ risk of pancreatitis
   Use only with extreme cautiona
   Neurotoxic drugs
↑ risk of neuropathy
   Use with cautionb
   Antacids containing magnesium or aluminum
↑ side effects associated
with antacid components
   Use caution with didanosine tablets for oral suspension and didanosine pediatric powder for oral solution
   Azole antifungals
↓ ketoconazole or
Itraconazole
concentration
   Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine.
   Quinolone antibiotics (see also ciprofloxacin in Table 9)
↓ quinolone concentration
   Consult package insert of the quinolone.
   Tetracycline antibiotics
↓ antibiotic concentration
   Consult package insert of the tetracycline.


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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


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Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin*, and Rifabutin*(CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz** (CYP450 Induction) Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)** (CYP450 Induction) Low dose Ritonavir (100 mg q12h)** (CYP450 Induction) Significantly Reduced Reduced Contraindicated Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin* (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated
Oral Contraceptives**containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of vorconazole and fluconazole Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs***(CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness


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Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz**(CYP3A4 Inhibition) Significantly Increased When voriconazole is coadministered with efavirenz, voriconazolemaintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition) Low dose Ritonavir (100 mg q12h)** No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine* (CYP3A4 Inhibition) AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate associated adverse events may be necessary [see Drug Interactions (7)]
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)]


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NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.


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Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and finasteride norfloxacin
   inhaled hydrocortisone ofloxacin
amoxicillin isoflurane omeprazole
ampicillin, with or without isoniazid prednisone, prednisolone
   sulbactam isradipine ranitidine
atenolol influenza vaccine rifabutin
azithromycin ketoconazole roxithromycin
caffeine, dietary ingestion lomefloxacin sorbitol
cefaclor mebendazole    (purgative doses do not
co-trimoxazole medroxyprogesterone    inhibit theophylline
   (trimethoprim and methylprednisolone    absorption)
   sulfamethoxazole) metronidazole sucralfate
diltiazem metoprolol terbutaline,systemic
dirithromycin nadolol terfenadine
enflurane nifedipine tetracycline
famotidine nizatidine tocainide
felodipine


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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0–24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


Table name:
Table 5 Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration with Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs) +82% +109%
Ketoconazole(400 mg once daily) +135% +164%


Table name:
Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism)
Drug or Drug Class Effect
Potential impact: Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Calcium Carbonate
Ferrous Sulfate
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Orlistat Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Bile Acid Sequestrants
-Colesevelam
-Cholestyramine
-Colestipol
Ion Exchange Resins
-Kayexalate
-Sevelamer
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels.
Other drugs:
Sucralfate
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone


Table name:
Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Effecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drugs That May Increase Serum Thyroxine-Binding Globulin (TBG) Concentration Drugs That May Decrease Serum TBG Concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs That May Cause Protein-Binding Site Displacement
Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations, and patients are likely clinically euthyroid.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
- Fenamates
- Phenylbutazone


Table name:
Table 4: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Drug or Drug Class Effect
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements.
Carbamazepine
Hydantoins
Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and FT4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Close monitoring of thyroid hormone parameters is recommended.
Other drugs:
Phenobarbital
Rifampin


Table name:
Table 5: Drugs That May Decrease Conversion of T4 to T3
Drug or Drug Class Effect
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day)
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.
Glucocorticoids
(e.g., Dexamethasone ≥ 4 mg/day)
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other:
Amiodarone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole,
posaconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, nefazodone,
gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2. Drug Interactions with PRIFTIN: Dosage Adjustment may be Necessary
Drug Class Examples of Drugs Within Class
Antiarrhythmics Disopyramide, mexiletine, quinidine, tocainide
Antibiotics Chloramphenicol, clarithromycin, dapsone, doxycycline;
Fluoroquinolones (such as ciprofloxacin)
Oral Anticoagulants Warfarin
Anticonvulsants Phenytoin
Antimalarials Quinine
Azole Antifungals Fluconazole, itraconazole, ketoconazole
Antipsychotics Haloperidol
Barbiturates Phenobarbital
Benzodiazepines Diazepam
Beta-Blockers Propanolol
Calcium Channel Blockers Diltiazem, nifedipine, verapamil
Cardiac Glycoside Preparations Digoxin
Corticosteroids Prednisone
Fibrates Clofibrate
Oral Hypoglycemics Sulfonylureas (e.g., glyburide, glipizide)
Hormonal Contraceptives/ Progestins Ethinyl estradiol, levonorgestrel
Immunosuppressants Cyclosporine, tacrolimus
Methylxanthines Theophylline
Narcotic analgesics Methadone
Phophodiesterase-5 (PDE-5) Inhibitors Sildenafil
Thyroid preparations Levothyroxine
Tricyclic antidepressants Amitriptyline, nortriptyline


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide ↓ lamotrigine ? CBZ epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


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Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list is not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants carbamazepine
Anti-HIV Agents indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide
Benzodiazepines alprazolam, diazepam, midazolam,For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics (repaglinide)
Opiate Analgesics fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals amphotericin B
Other ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide
   
Decrease plasma concentration of itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents nevirapine, efavirenz
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
   
Increase plasma concentration of itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Anti-HIV Agents indinavir, ritonavir


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Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics pimozide
Antiarrhythmics dofetilide, quinidine
Benzodiazepines oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers Nisoldipine, felodipine
Ergot Alkaloids dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors lovastatin, simvastatin
Opiate Analgesics levacetylmethadol (levomethadyl), methadone


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Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.


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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL phenytoina, warfarinb
Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


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  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


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Table 2: Drug-Thyroidal Axis Interactions
  Drug or Drug Class   Effect
  Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
 Dopamine / Dopamine Agonists Glucocorticoids Octreotide

 Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
  Drugs that alter thyroid hormone secretion
  Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
 Aminoglutethimide Amiodarone Iodide(including iodine-containing   Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide







 Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
  Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
 Amiodarone Iodide(including iodine-containing      Radiographic contrast agents)

 Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
  Drugs that may decrease T 4 absorption, which may result in hypothyroidism
 Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










 Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
  Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
 Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





 Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


  Drugs that may cause protein-binding site displacement
 Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)





 Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
 Carbamazepine Hydantoins Phenobarbital Rifampin


 Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
  Drugs that may decrease T 4 5’-deiodinase activity
 Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




 Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T   levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
  Miscellaneous
 Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

 Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
 Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors   (SSRIs; e.g., Sertraline)



 Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
 Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin




 Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
 Cardiac Glycosides  Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
 Cytokines - Interferon-α - Interleukin-2

 Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
 Growth Hormones - Somatrem - Somatropin

 Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
 Ketamine  Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
 Methylxanthine Bronchodilators - (e.g., Theophylline)
 Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
 Radiographic Agents  Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
 Sympathomimetics  Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
 Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









 These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio * ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Reevaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day - 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed



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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and finasteride norfloxacin
  inhaled hydrocortisone ofloxacin
amoxicillin isoflurane omeprazole
ampicillin, with or without isoniazid prednisone, prednisolone
  sulbactam isradipine ranitidine
atenolol influenza vaccine rifabutin
azithromycin ketoconazole roxithromycin
caffeine, dietary ingestion lomefloxacin sorbitol
cefaclor mebendazole   (purgative doses do not
co-trimoxazole medroxyprogesterone   inhibit theophylline
  (trimethoprim and methylprednisolone   absorption)
  sulfamethoxazole) metronidazole sucralfate
diltiazem metoprolol terbutaline,systemic
dirithromycin nadolol terfenadine
enflurane nifedipine tetracycline
famotidine nizatidine tocainide
felodipine


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)